ES2297864T3 - REPLACED PIRROLOPIRIMIDINES AND PROCESSES FOR THEIR PREPARATION. - Google Patents
REPLACED PIRROLOPIRIMIDINES AND PROCESSES FOR THEIR PREPARATION. Download PDFInfo
- Publication number
- ES2297864T3 ES2297864T3 ES97940108T ES97940108T ES2297864T3 ES 2297864 T3 ES2297864 T3 ES 2297864T3 ES 97940108 T ES97940108 T ES 97940108T ES 97940108 T ES97940108 T ES 97940108T ES 2297864 T3 ES2297864 T3 ES 2297864T3
- Authority
- ES
- Spain
- Prior art keywords
- formula
- pyrrolo
- pyrimidine
- chloroanilino
- radical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 50
- 238000002360 preparation method Methods 0.000 title claims description 42
- 230000008569 process Effects 0.000 title claims description 38
- -1 3 -phenylureido Chemical group 0.000 claims abstract description 212
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 67
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 239000000460 chlorine Substances 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims abstract description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 9
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical class N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims abstract description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims abstract description 5
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 claims abstract description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 4
- 125000005281 alkyl ureido group Chemical group 0.000 claims abstract description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims abstract 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 204
- 125000001424 substituent group Chemical group 0.000 claims description 54
- 125000006239 protecting group Chemical group 0.000 claims description 51
- 239000002253 acid Substances 0.000 claims description 49
- 125000000524 functional group Chemical group 0.000 claims description 26
- 229910052740 iodine Inorganic materials 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 230000001012 protector Effects 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Chemical group 0.000 claims description 7
- 230000006870 function Effects 0.000 claims description 7
- BYYLPECJKOEHBV-UHFFFAOYSA-N 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde Chemical compound ClC1=CC=CC(NC=2C=3C=C(C=O)NC=3N=CN=2)=C1 BYYLPECJKOEHBV-UHFFFAOYSA-N 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 6
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 6
- 150000001448 anilines Chemical class 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- BNMRACHWXQYRHO-UHFFFAOYSA-N 4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidine-6-carbothioamide Chemical compound N1=CN=C2NC(C(=S)N)=CC2=C1NC1=CC=CC(Cl)=C1 BNMRACHWXQYRHO-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- OGEBYZFAAZVIHT-UHFFFAOYSA-N N-(3-chlorophenyl)-6-(2H-tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C=2NN=NN=2)=C1 OGEBYZFAAZVIHT-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 3
- 150000001351 alkyl iodides Chemical class 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 3
- 150000002443 hydroxylamines Chemical class 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- YYELWCZQXDCXCI-UHFFFAOYSA-N 1-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-3-ethylurea Chemical compound CCNC(=O)NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 YYELWCZQXDCXCI-UHFFFAOYSA-N 0.000 claims description 2
- UTIXVEICQYJJRY-UHFFFAOYSA-N 1-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-3-methylthiourea Chemical compound CNC(=S)NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 UTIXVEICQYJJRY-UHFFFAOYSA-N 0.000 claims description 2
- TWNRMTYWTBYQQS-UHFFFAOYSA-N 1-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-3-ethylurea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 TWNRMTYWTBYQQS-UHFFFAOYSA-N 0.000 claims description 2
- UCRKSQGCZVGBGX-UHFFFAOYSA-N 1-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-3-methylthiourea Chemical compound C1=CC(NC(=S)NC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 UCRKSQGCZVGBGX-UHFFFAOYSA-N 0.000 claims description 2
- CGSVJQVCEGIWCF-OAHLLOKOSA-N 1-ethyl-3-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]urea Chemical compound CCNC(=O)NC1=CC=CC(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)=C1 CGSVJQVCEGIWCF-OAHLLOKOSA-N 0.000 claims description 2
- YPCURGZEPMFYLX-OAHLLOKOSA-N 1-ethyl-3-[4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C(NC1=NC=N2)=CC1=C2N[C@H](C)C1=CC=CC=C1 YPCURGZEPMFYLX-OAHLLOKOSA-N 0.000 claims description 2
- VEJBANJNCNEZHG-CQSZACIVSA-N 1-methyl-3-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]thiourea Chemical compound CNC(=S)NC1=CC=CC(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)=C1 VEJBANJNCNEZHG-CQSZACIVSA-N 0.000 claims description 2
- CYMAZKIEYPVYOH-UHFFFAOYSA-N 2-methoxy-4-[4-(3-methylanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound C1=C(O)C(OC)=CC(C=2NC3=NC=NC(NC=4C=C(C)C=CC=4)=C3C=2)=C1 CYMAZKIEYPVYOH-UHFFFAOYSA-N 0.000 claims description 2
- VAKYVBRASQJLDI-UHFFFAOYSA-N 2-methylpropyl n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCC(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 VAKYVBRASQJLDI-UHFFFAOYSA-N 0.000 claims description 2
- JEWOIKNJTXJTGH-UHFFFAOYSA-N 4-(4-anilino-7h-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenol;hydrochloride Chemical compound Cl.C1=C(O)C(OC)=CC(C=2NC3=NC=NC(NC=4C=CC=CC=4)=C3C=2)=C1 JEWOIKNJTXJTGH-UHFFFAOYSA-N 0.000 claims description 2
- WXZNMFZVZMNGIO-UHFFFAOYSA-N 4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]-2-methoxyphenol;hydrochloride Chemical compound Cl.C1=C(O)C(OC)=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 WXZNMFZVZMNGIO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- VGFSMURRDQKEKB-UHFFFAOYSA-N 6-(3-methoxy-4-phenylmethoxyphenyl)-n-(3-methylphenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound COC1=CC(C=2NC3=NC=NC(NC=4C=C(C)C=CC=4)=C3C=2)=CC=C1OCC1=CC=CC=C1 VGFSMURRDQKEKB-UHFFFAOYSA-N 0.000 claims description 2
- QOLIVYYSALQXGF-LJQANCHMSA-N 6-[3-(benzylamino)phenyl]-n-[(1r)-1-phenylethyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C(C=1)=CC=CC=1NCC1=CC=CC=C1 QOLIVYYSALQXGF-LJQANCHMSA-N 0.000 claims description 2
- NIFHYNGZYDVDBU-UHFFFAOYSA-N 6-[4-(benzylamino)phenyl]-n-(3-chlorophenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C=2C=CC(NCC=3C=CC=CC=3)=CC=2)=C1 NIFHYNGZYDVDBU-UHFFFAOYSA-N 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- QOPHSBUZTVLVBJ-UHFFFAOYSA-N N-(3-chlorophenyl)-6-(1-methyltetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound CN1N=NN=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 QOPHSBUZTVLVBJ-UHFFFAOYSA-N 0.000 claims description 2
- BCZCVGXQOLPACI-UHFFFAOYSA-N N-(3-chlorophenyl)-6-(2-methyltetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound CN1N=NC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=N1 BCZCVGXQOLPACI-UHFFFAOYSA-N 0.000 claims description 2
- GAABGZUDSKAVGH-UHFFFAOYSA-N N-(3-chlorophenyl)-6-(4,5-dimethyl-1,3-thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound S1C(C)=C(C)N=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 GAABGZUDSKAVGH-UHFFFAOYSA-N 0.000 claims description 2
- ZRSLTYRSYOZHIR-UHFFFAOYSA-N N-(3-chlorophenyl)-6-(4-ethyl-1,3-thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound CCC1=CSC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=N1 ZRSLTYRSYOZHIR-UHFFFAOYSA-N 0.000 claims description 2
- BPEIBTXCKPKWLE-UHFFFAOYSA-N N-(3-chlorophenyl)-6-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1C1=CSC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=N1 BPEIBTXCKPKWLE-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- NUXWAOSDMYECDX-UHFFFAOYSA-N ethyl n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 NUXWAOSDMYECDX-UHFFFAOYSA-N 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 150000002540 isothiocyanates Chemical class 0.000 claims description 2
- ROZJWSLFOMITNR-UHFFFAOYSA-N methyl n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 ROZJWSLFOMITNR-UHFFFAOYSA-N 0.000 claims description 2
- SDSLGPIDULPJQG-MRXNPFEDSA-N n,n-dimethyl-n'-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methanimidamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=CC(N=CN(C)C)=C1 SDSLGPIDULPJQG-MRXNPFEDSA-N 0.000 claims description 2
- PRVIBBCNUUBOSX-UHFFFAOYSA-N n-(3-chlorophenyl)-6-(1,3-thiazol-2-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C=2SC=CN=2)=C1 PRVIBBCNUUBOSX-UHFFFAOYSA-N 0.000 claims description 2
- LIPUGMMVKJZMRG-UHFFFAOYSA-N n-(3-chlorophenyl)-6-(3-methoxy-4-phenylmethoxyphenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound COC1=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=CC=C1OCC1=CC=CC=C1 LIPUGMMVKJZMRG-UHFFFAOYSA-N 0.000 claims description 2
- GBCGNNNFIRWGCW-UHFFFAOYSA-N n-(3-chlorophenyl)-6-[4-[(4-methylpiperazin-1-yl)methylideneamino]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1CN(C)CCN1C=NC1=CC=C(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)C=C1 GBCGNNNFIRWGCW-UHFFFAOYSA-N 0.000 claims description 2
- ROLDUDKLNYYONL-UHFFFAOYSA-N n-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]ethanesulfonamide Chemical compound CCS(=O)(=O)NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 ROLDUDKLNYYONL-UHFFFAOYSA-N 0.000 claims description 2
- RBEFWIDYHAIBSL-UHFFFAOYSA-N n-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 RBEFWIDYHAIBSL-UHFFFAOYSA-N 0.000 claims description 2
- PKNAMUVGIGLHAY-UHFFFAOYSA-N n-[3-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)NC1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 PKNAMUVGIGLHAY-UHFFFAOYSA-N 0.000 claims description 2
- WVICNPJYDFMIGL-OAHLLOKOSA-N n-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]ethanesulfonamide Chemical compound CCS(=O)(=O)NC1=CC=CC(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)=C1 WVICNPJYDFMIGL-OAHLLOKOSA-N 0.000 claims description 2
- KQWSURRAHQPGAF-CQSZACIVSA-N n-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methanesulfonamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=CC(NS(C)(=O)=O)=C1 KQWSURRAHQPGAF-CQSZACIVSA-N 0.000 claims description 2
- WLMINMLKCZPIDN-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]benzenesulfonamide Chemical compound ClC1=CC=CC(NC=2C=3C=C(NC=3N=CN=2)C=2C=CC(NS(=O)(=O)C=3C=CC=CC=3)=CC=2)=C1 WLMINMLKCZPIDN-UHFFFAOYSA-N 0.000 claims description 2
- NDIAGRBKTSAOQM-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propane-2-sulfonamide Chemical compound C1=CC(NS(=O)(=O)C(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 NDIAGRBKTSAOQM-UHFFFAOYSA-N 0.000 claims description 2
- ZXEAZQRLYXDOIU-OAHLLOKOSA-N n-[4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]ethanesulfonamide Chemical compound C1=CC(NS(=O)(=O)CC)=CC=C1C(NC1=NC=N2)=CC1=C2N[C@H](C)C1=CC=CC=C1 ZXEAZQRLYXDOIU-OAHLLOKOSA-N 0.000 claims description 2
- KJPHJVDDQOMOSH-MRXNPFEDSA-N n-[4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propane-2-sulfonamide Chemical compound C1=CC(NS(=O)(=O)C(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2N[C@H](C)C1=CC=CC=C1 KJPHJVDDQOMOSH-MRXNPFEDSA-N 0.000 claims description 2
- MKLSHESXKCZSML-UHFFFAOYSA-N propan-2-yl n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 MKLSHESXKCZSML-UHFFFAOYSA-N 0.000 claims description 2
- JJJQHTCJNMSSJV-UHFFFAOYSA-N pyrrolo[2,3-d]pyrimidin-4-one Chemical class O=C1N=CN=C2N=CC=C12 JJJQHTCJNMSSJV-UHFFFAOYSA-N 0.000 claims description 2
- 150000004943 pyrrolo[2,3-d]pyrimidines Chemical class 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- LDUVGYTUBRSPKL-UBKPWBPPSA-N (NE)-N-[[4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methylidene]hydroxylamine Chemical compound N1=CN=C2NC(/C=N/O)=CC2=C1NC1=CC=CC(Cl)=C1 LDUVGYTUBRSPKL-UBKPWBPPSA-N 0.000 claims 1
- LDUVGYTUBRSPKL-FMQZQXMHSA-N (NZ)-N-[[4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methylidene]hydroxylamine Chemical compound N1=CN=C2NC(\C=N/O)=CC2=C1NC1=CC=CC(Cl)=C1 LDUVGYTUBRSPKL-FMQZQXMHSA-N 0.000 claims 1
- IKELJGAIXVSXJM-CQSZACIVSA-N 1-methyl-3-[4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]thiourea Chemical compound C1=CC(NC(=S)NC)=CC=C1C(NC1=NC=N2)=CC1=C2N[C@H](C)C1=CC=CC=C1 IKELJGAIXVSXJM-CQSZACIVSA-N 0.000 claims 1
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- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 208000032839 leukemia Diseases 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
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- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- LLCOIQRNSJBFSN-UHFFFAOYSA-N methane;sulfurochloridic acid Chemical compound C.OS(Cl)(=O)=O LLCOIQRNSJBFSN-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical compound COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000003641 microbiacidal effect Effects 0.000 description 1
- 229940124561 microbicide Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
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- 239000011707 mineral Substances 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 description 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
- RCOAJPOHJGOPPC-UHFFFAOYSA-N n-(3-chlorophenyl)-6-(3-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound [O-][N+](=O)C1=CC=CC(C=2NC3=NC=NC(NC=4C=C(Cl)C=CC=4)=C3C=2)=C1 RCOAJPOHJGOPPC-UHFFFAOYSA-N 0.000 description 1
- DZRXPIWDNCNPOM-MRXNPFEDSA-N n-[3-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)NC1=CC=CC(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)=C1 DZRXPIWDNCNPOM-MRXNPFEDSA-N 0.000 description 1
- RJHPCDDFUQAQPU-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]ethanesulfonamide Chemical compound C1=CC(NS(=O)(=O)CC)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 RJHPCDDFUQAQPU-UHFFFAOYSA-N 0.000 description 1
- WBVNHFVJQUXGDJ-UHFFFAOYSA-N n-[4-[4-(3-chloroanilino)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methanesulfonamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C(NC1=NC=N2)=CC1=C2NC1=CC=CC(Cl)=C1 WBVNHFVJQUXGDJ-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical class CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 238000004810 partition chromatography Methods 0.000 description 1
- 235000015927 pasta Nutrition 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000014483 powder concentrate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- HLIBNTOXKQCYMV-UHFFFAOYSA-N propylsulfamic acid Chemical compound CCCNS(O)(=O)=O HLIBNTOXKQCYMV-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 1
- 150000004944 pyrrolopyrimidines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- RZWQDAUIUBVCDD-UHFFFAOYSA-M sodium;benzenethiolate Chemical compound [Na+].[S-]C1=CC=CC=C1 RZWQDAUIUBVCDD-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940057429 sorbitan isostearate Drugs 0.000 description 1
- 229950004959 sorbitan oleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Un derivado de 7H-pirrolo[2,3-d]pirimidina de fórmula I (Ver fórmula) En el cual N es 0 o 1, Q es 0 o 1 R es cloro R1 es hidrógeno R2 es a) un radical de fórmula II (Ver fórmula) En el cual u es 1 y R4 es N 3 -alquilureido inferior, N 3 -fenilureido, N 3 -alquiltioureido, alquilcarbonilamino inferior, benziloxicarbonilamino, morfolina-4-carbonilo, piperazina-1-carbonilo, 4alquilpiperazina inferior-1-carbonilo, alquilsulfonilamino inferior, benzenosulfonilamino, toluenosulfonilamino, furan-2-carbonilamino, tiofeno-2- carbonilamino, benzilamino, hidroximetil o un radical de fórmula -N=C(R5)-R6 es el cual R5 es hidrógeno o alquilo inferior y R6 es di-alquilamino inferior, piperidino, 4-alquilpiperazino o morfolino inferior, o es b) un radical de fórmula III (Ver fórmula) en el cual R7 es alcoxi inferior y R8 es hidroxilo o benziloxi, o es c) piperazino-1-carbonilo, 4-alquilpiperazino inferior-1-carbonilo, morfolino-4-carbonilo, tiocarbamoilo, tiazol- 2-il, 4-(4-metoxifenil)tiazol-2-il, 4-etiltiazol-2-il, 4,5-dimetiltiazol-2-il, tetrazol-5-il, 2metiltetrazol-5-il o 1-metiltetrazol-5-il, o es d) un radical de fórmula -CH=H-OR9 en el cual R9 es hidrógeno o alquilo inferior, y R3 es hidrógeno o alquilo inferior, o una sal farmacéuticamente aceptable de este, En donde el sufijo ¿inferior¿ denota un radical que tiene hasta y que incluye un máximo de 7 átomos de carbono.A derivative of 7H-pyrrolo [2,3-d] pyrimidine of formula I (See formula) In which N is 0 or 1, Q is 0 or 1 R is chlorine R1 is hydrogen R2 is a) a radical of formula II (See formula) In which u is 1 and R4 is N 3-lower alkylureido, N 3 -phenylureido, N 3-alkylthioureido, lower alkylcarbonylamino, benzyloxycarbonylamino, morpholine-4-carbonyl, piperazine-1-carbonyl, 4-lower alkylpiperazine-1 -carbonyl, lower alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, furan-2-carbonylamino, thiophene-2-carbonylamino, benzylamino, hydroxymethyl or a radical of formula -N = C (R5) -R6 is which R5 is hydrogen or lower alkyl and R6 it is di-lower alkylamino, piperidino, 4-alkylpiperazino or lower morpholino, or is b) a radical of formula III (See formula) in which R7 is lower alkoxy and R8 is hydroxy or benzyloxy, or is c) piperazino-1- carbonyl, 4-lower alkylpiperazino-1-carbonyl, morpholino-4-carbonyl, thiocarbamoyl, thiazol-2-yl, 4- (4-methoxyphenyl) thiazole -2-yl, 4-ethylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl or 1-methyltetrazol-5-yl, or is d) a radical of formula -CH = H-OR9 in which R9 is hydrogen or lower alkyl, and R3 is hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof, wherein the suffix "lower" denotes a radical having up to and including a maximum of 7 carbon atoms.
Description
Pirrolopirimidinas sustituidas y procesos para su preparación.Substituted pyrrolopyrimidines and processes for its preparation.
La invención se relaciona con derivados de 7H-pirrolo[2,3-d]pirimidina y con procesos e intermedios novedosos para su preparación, con formulaciones farmacéuticas que comprenden tales derivados y con el uso de tales derivados como medicamentos.The invention relates to derivatives of 7H-pyrrolo [2,3-d] pyrimidine and with innovative processes and intermediates for its preparation, with pharmaceutical formulations comprising such derivatives and with the use of such derivatives as medicines.
La invención se relaciona con derivados de 7H-pirrolo[2,3-d]pirimidina de la fórmula IThe invention relates to derivatives of 7H-pyrrolo [2,3-d] pyrimidine of the formula I
en el cualat which
n es 0 o 1,n is 0 or 1,
q es 0 o 1,which is 0 or 1,
R es cloro,R is chlorine,
R_{1} es hidrógeno,R1 is hydrogen,
R_{2} esR2 is
- a)to)
- un radical de fórmula IIa radical of formula II
- en el cual u es 1 yin which u is 1 and
- R_{4} es N^{3}-alquilureido inferior, N^{3}-fenilureido, N^{3}-alquiltioureido inferior, alcoxicarbonilamino inferior, benziloxicarbonilamino, morfolino-4-carbonilo, piperazino-1-carbonilo, 4-alquilpiperazina inferior-1-carbonilo, alquilsulfonilamino inferior, bencenosulfonilamino, toluenosulfonilamino, furan-2-carbonilamino, tiofeno-2-carbonilamino, bencilamino, hidroximetilo o un radical de fórmula -N=C(R_{5})-R_{6} en el cual R_{5} es hidrógeno o alquilo inferior y R_{6} es dialquilamino inferior, piperidino, 4-alquilpiperazino inferior o morfolino, o esR_ {4} is N3-lower alkylureido, N3 -phenylureido, N 3 -alkyl lower alkyl, lower alkoxycarbonylamino, benzyloxycarbonylamino, morpholino-4-carbonyl, piperazino-1-carbonyl, 4-alkylpiperazine lower-1-carbonyl, lower alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, furan-2-carbonylamino, thiophene-2-carbonylamino, benzylamino, hydroxymethyl or a radical of formula -N = C (R 5) - R 6 in which R 5 is hydrogen or lower alkyl and R 6 is lower dialkylamino, piperidino, 4-lower alkylpiperazino or morpholino, or is it
- b)b)
- un radical de la fórmula IIIa radical of formula III
- en el cual R_{7} es alcoxi inferior y R_{8} es hidroxilo o benciloxi, o esin which R 7 is lower alkoxy and R 8 is hydroxyl or benzyloxy, or is
- c)C)
- piperazina-1-carbonilo, 4-alquilpiperazina inferior-1-carbonilo, morfolino-4-carbonilo, tiocarbamoilo, tiazol-2-ilo, 4-(4-metoxifenil)tiazol-2-ilo, 4-etiltiazol-2-ilo, 4,5-dimetiltiazol-2-ilo, tetrazol-5-ilo, 2-metiltetrazol-5-ilo o 1-metiltetrazol-5-ilo, o espiperazine-1-carbonyl, 4-alkylpiperazine lower-1-carbonyl, morpholino-4-carbonyl, thiocarbamoyl, thiazol-2-yl, 4- (4-methoxyphenyl) thiazol-2-yl, 4-ethylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl or 1-methyltetrazol-5-yl, or is it
- d)d)
- un radical de fórmula -CH=N-OR_{9}, en el cual R_{9} es hidrógeno o alquilo inferior, ya radical of formula -CH = N-OR9, in which R 9 is hydrogen or lower alkyl, and
R_{3} es hidrógeno o alquilo inferior,R 3 is hydrogen or lower alkyl,
o una sal farmacéuticamente aceptable de ésteor a pharmaceutically acceptable salt of East
en donde el prefijo "inferior" denota un radical que tiene hasta e incluye un máximo de 7 átomos de carbono.where the "lower" prefix denotes a radical that has up to and includes a maximum of 7 atoms of carbon.
El prefijo "inferior" utilizado anteriormente y posteriormente denota un radical que tiene hasta y que incluye un máximo de 7, especialmente hasta que incluye un máximo de 4, y en particular que tiene 1 o 2, átomos de carbono.The "lower" prefix used earlier and later denotes a radical that has up to and which includes a maximum of 7, especially until it includes a maximum of 4, and in particular having 1 or 2, atoms of carbon.
Preferiblemente, n es 0 o especialmente 1. Cunado existe solamente un sustituyente R, este sustituyente está preferiblemente en la posición 3 del anillo de fenilo. Cuando dos sustituyentes R están presentes, estos sustituyentes están preferiblemente en las posiciones 3 y 4.Preferably, n is 0 or especially 1. When there is only one R substituent, this substituent is preferably in position 3 of the phenyl ring. When two R substituents are present, these substituents are preferably in positions 3 and 4.
El halógeno R es bromo, yodo o preferiblemente fluor o cloro. Cuando n es 1, R es preferiblemente cloro.The halogen R is bromine, iodine or preferably fluorine or chlorine When n is 1, R is preferably chlorine.
Alquilo inferior es, por ejemplo, metilo.Lower alkyl is, for example, methyl.
Alcanoiloxi inferior es, por ejemplo, acetoxi.Lower alkanoyloxy is, for example, acetoxy.
Alcoxi inferior es, por ejemplo, metoxi.Lower alkoxy is, for example, methoxy.
Alcanoilo inferior es, por ejemplo, acetilo.Lower alkanoyl is, for example, acetyl.
Alcoxicarbonilo inferior es, por ejemplo, metoxicarbonilo.Lower alkoxycarbonyl is, for example, methoxycarbonyl
Alquilcarbamoilo N-inferior es, por ejemplo, N-metilcarbamoilo, N-(n-butil)carbamoilo o N-(3-metilbut-1-il)carbamoilo.N-lower alkylcarbamoyl is, for example, N-methylcarbamoyl, N- (n-butyl) carbamoyl or N- (3-methylbut-1-yl) carbamoyl.
N,N-Di-alquilcarbamoilo inferior es, por ejemplo, N,N-di-metilcarbamoilo.N, N-Di-alkylcarbamoyl lower is for example N, N-di-methylcarbamoyl.
Alcanoilamino inferior es, por ejemplo, acetilamino.Lower alkanoylamino is, for example, acetylamino
Alquilamino inferior es, por ejemplo, metilamino.Lower alkylamino is, for example, methylamino
N,N-Di-alquilamino inferior es, por ejemplo, dimetilamino.N, N-Di-alkylamino Lower is, for example, dimethylamino.
Alcoxicarbonilmetoxi inferior es, por ejemplo, metoxicarbonilmetoxi.Lower alkoxycarbonylmethoxy is, for example, methoxycarbonylmethoxy.
El radical R_{1} es preferiblemente hidrógeno.The radical R1 is preferably hydrogen.
El símbolo u es preferiblemente 1. En este caso, el radical R_{4} está preferiblemente en la posición 3 o 4 del anillo de fenilo.The symbol u is preferably 1. In this case, the radical R 4 is preferably in position 3 or 4 of the phenyl ring
Amidino es un radical de la fórmula -C(=NH)-NH_{2}.Amidino is a radical of the formula -C (= NH) -NH2.
Guanidino es un radical de la fórmula -NH-C(=NH)-NH_{2}.Guanidino is a radical of the formula -NH-C (= NH) -NH2.
Ureido es un radical de la fórmula -NH-C(=O)-NH_{2}.Ureido is a radical of the formula -NH-C (= O) -NH2.
N^{3}-Alquilo inferior ureido es un radical de la fórmula -NH-C(=O)-NH-alquilo inferior, preferiblemente N^{3}-etilureido.N3 -Ulido lower alkyl it is a radical of the formula -NH-C (= O) -NH-alkyl lower, preferably N 3 -ethylureido.
N^{3},N^{3}-Di-alquilureido inferior es un radical de la fórmula -NH-C(=O)-N(alquilo inferior)_{2}.N 3, N 3 -Di-alkylureido lower is a radical of the formula -NH-C (= O) -N (alkyl lower) 2.
N^{3}-Fenilureido es un radical de la fórmula -NH-C(=O)-NH-fenilo.N3 -Fenilureide is a formula radical -NH-C (= O) -NH-phenyl.
N^{3},N^{3}-Difenilureido es un radical de la fórmula -NH-C(=O)-N(fenilo)_{2}.N 3, N 3 -Diphenylureido is a radical of the formula -NH-C (= O) -N (phenyl) 2.
Tioureido es un radical de la fórmula -NH-C(=S)-NH_{2}.Tioureido is a radical of the formula -NH-C (= S) -NH2.
N^{3}-Alquiltioureido inferior es un radical de la fórmula -NH-C(=S)-NH-alquilo inferior, preferiblemente N^{3}-metiltioureido.N3-Lower alkylthioureido it is a radical of the formula -NH-C (= S) -NH-alkyl lower, preferably N 3 -methylthioureide.
N^{3},N^{3}-Di-alquiltioureido inferior es un radical de la fórmula -NH-C(=S)-N(alquilo inferior)_{2}.N 3, N 3 -Di-alkylthioureido lower is a radical of the formula -NH-C (= S) -N (alkyl lower) 2.
Alcoxicarbonilamino inferior es, por ejemplo, metoxicarbonilamino, etoxicarbonilamino, isopropiloxicarbonilamino o 2-metilpropiloxicarbonilamino.Lower alkoxycarbonylamino is, for example, methoxycarbonylamino, ethoxycarbonylamino, isopropyloxycarbonylamino or 2-methylpropyloxycarbonylamino.
Morfolino-4-carbonilo también se denomina morfolinocarbonilo.Morpholino-4-Carbonyl It is also called morpholinocarbonyl.
4-alquilpiperazina inferior-1-carbonilo es preferiblemente 4-metilpiperazina-1-carbonilo. Alquilsuflonilamino inferior es preferiblemente metilsulfonilamino, etilsulfonilamino o isopropilsulfonilamino.4-alkylpiperazine lower-1-carbonyl is preferably 4-methylpiperazine-1-carbonyl. Lower alkylsuflonylamino is preferably methylsulfonylamino, ethylsulfonylamino or isopropylsulfonylamino.
El radical de la fórmula -N=C(R_{5})-R_{6}, en el cual R_{5} es hidrógeno y R_{6} es di-alquilamino inferior, se denomina di-alquilaminometilenamino inferior. Los radicales correspondientes en los cuales R_{6} es piperidino, 4-alquilpiperazino inferior o morfolino se denominan los radicales R_{6}-metilenamino, en el cual R_{6} se define como anteriormente, por ejemplo, como piperidinometilamino.The radical of the formula -N = C (R 5) - R 6, in which R 5 is hydrogen and R 6 is di-lower alkylamino, it called di-lower alkylaminomethylene amine. The corresponding radicals in which R 6 is piperidino, 4-lower alkylpiperazino or morpholino are called the radicals R 6 -methyleneamino, in which R_ {6} is defined as above, for example, as piperidinomethylamino.
R_{5} es preferiblemente hidrógeno.R 5 is preferably hydrogen.
Di-alquilamino inferior R_{6} es preferiblemente dimetilamino o dietilamino.Di-lower alkylamino R 6 It is preferably dimethylamino or diethylamino.
4-alquilpiperazino inferior es 4-alquilpiperazino inferior-1-ilo, preferiblemente 4-metilpiperazin-1-ilo. Morfolino es 4-morfolinilo.4-lower alkylpiperazino is 4-alkylpiperazino lower-1-yl, preferably 4-methylpiperazin-1-yl. Morpholino is 4-morpholinyl.
Alcoxi inferior R_{7} es preferiblemente metoxi.Lower alkoxy R 7 is preferably methoxy
Amino-alquilo inferior R_{1} o R_{2} cuyo grupo amino se sustituye por uno o dos hidroxi-alquilo inferior, amino-alquilo inferior, carboxi-alquilo inferior, alcoxicarbonilo inferior-alquilo inferior, benziloxicarbonilo-alquilo inferior o los radicales bencilo que en la porción fenilo son no sustituidos o sustituidos por halógeno, alquilo inferior, hidroximetilo, aminometilo, hidroxilo, alcanoiloxi inferior, alcoxi inferior, carboxilo, alcanoilo inferior, benzoilo, alcoxicarbonilo inferior, carbamoilo, N-alquilcarbamoilo inferior, N,N-di-alquilcarbamoilo inferior, ciano, amino, alcanoilamino inferior, alquilamino inferior, N,N-di-alquilamino inferior o trifluorometilo, es preferiblemente apropiadamente aminometilo sustituido.Amino-lower alkyl R 1 or R2 whose amino group is replaced by one or two hydroxy lower alkyl, lower amino-alkyl, carboxy-lower alkyl, alkoxycarbonyl lower-lower alkyl, benzyloxycarbonyl-lower alkyl or radicals benzyl which in the phenyl portion are unsubstituted or substituted by halogen, lower alkyl, hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or trifluoromethyl, is preferably appropriately aminomethyl replaced.
Amino-alquilo inferior R_{1} o R_{2} cuyo grupo amino es sustituido por uno o dos radicales hidroxi-alquilo inferior es preferiblemente, por ejemplo, un radical de fórmula -CH_{2}-NH(CH_{2}-CH_{2})_{2}.Amino-lower alkyl R 1 or R2 whose amino group is substituted by one or two radicals hydroxy-lower alkyl is preferably, by example, a radical of formula -CH 2 -NH (CH 2 -CH 2) 2.
Amino-alquilo inferior R_{1} o R_{2} cuyo grupo amino es sustituido por uno o dos radicales bencilo el cual en la porción fenilo son no sustituidos o sustituidos por halógeno, alquilo inferior, hidroximetilo, aminometilo, hidroxilo, alcanoiloxi inferior, alcoxi inferior, carboxilo, alcanoilo inferior, benzoilo, alcoxicarbonilo inferior, carbamoilo, N-alquilcarbamoilo inferior, N,N-di-alquilcarbamoilo inferior, ciano, amino, alcanoilamino inferior, alquilamino inferior, N,N-di-alquilamino inferior o trifluorometilo, es preferiblemente, por ejemplo, un radical de fórmula -CH_{2}-NH-CH_{2}-C_{6}H_{4}-OCH_{3},Amino-lower alkyl R 1 or R2 whose amino group is substituted by one or two radicals benzyl which in the phenyl portion are unsubstituted or substituted by halogen, lower alkyl, hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl, lower N-alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or trifluoromethyl, is preferably, for example, a radical of formula -CH 2 -NH-CH 2 -C 6 H 4 -OCH 3,
Tal como, en particular, 4-metoxifenilmetilaminometilo, o 4-hidroxifenilmetilaminometilo.Such as, in particular, 4-methoxyphenylmethylaminomethyl, or 4-hydroxyphenylmethylaminomethyl.
Tiocarbamoilo es el radical de fórmula -C(=S)-NH_{2} y también se denomina aminotiocarbonilo.Thiocarbamoyl is the radical of formula -C (= S) -NH_ {2} and is also called aminothiocarbonyl.
Un radical heterocíclico R_{1} o R_{2} unido por vía de un átomo de anillo de carbono y que tiene cinco miembros de anillo y 1-4 heteroátomos por anillo, seleccionado de oxígeno, nitrógeno y azufre, es no sustituido o sustituido, por ejemplo, pirrolilo, tienilo, furilo o preferiblemente tetrazol-5-ilo que es no sustituido o sustituido por alquilo inferior, o tiazol-2-ilo que es no sustituido o sustituido por alcoxifenilo inferior, por ejemplo, tiazol-2-ilo, 4-(4-metoxifenil)tiazol-2-ilo, 4-etiltiazol-2-ilo o 4,5-dimetiltiazol-2-ilo.A heterocyclic radical R 1 or R 2 attached via a carbon ring atom and that has five members of ring and 1-4 heteroatoms per ring, selected from oxygen, nitrogen and sulfur, it is unsubstituted or substituted, for example, pyrrolyl, thienyl, furyl or preferably tetrazol-5-yl which is unsubstituted or substituted by lower alkyl, or thiazol-2-yl which is unsubstituted or substituted by lower alkoxyphenyl, for example, thiazol-2-yl, 4- (4-methoxyphenyl) thiazol-2-yl, 4-ethylthiazol-2-yl or 4,5-dimethylthiazol-2-yl.
Tetrazol-5-ilo es 1 H-tetrazol-5-ilo o 2H-tetrazol-5-ilo tautomérico o una mezcla de estas dos formas tautoméricas. El tetrazol-5-ilo sustituido por alquilo inferior es N^{1}-alquiltetrazol inferior o N^{2}-alquiltetrazol inferior-5-ilo, en particular 1-metiiltetrazol-5-ilo o 2-metiltetrazol-5-ilo.Tetrazol-5-yl is 1 H-tetrazol-5-yl or 2H-tetrazol-5-yl tautomeric or a mixture of these two tautomeric forms. He tetrazol-5-yl substituted by lower alkyl is N1-lower alkyltetrazole or N2-alkyltetrazol lower-5-yl, in particular 1-methyltetrazol-5-yl or 2-methyltetrazol-5-yl.
Un radical heterocíclico diferente de piperazinilo y que tiene cinco o seis miembros pr anillo y 1-4 heteroátomos por anillo, seleccionados de oxígeno, nitrógeno y azufre, es tal radical no sustituido o sustituido, por ejemplo, pirrolilo, tienilo, furilo, tetrazol-5-ilo el cual es no sustituido o sustituido por alquilo inferior; tiazol-2-ilo el cual es no sustituido o sustituido por alcoxifenilo inferior, o morfolino o 4-alquilpiperazin inferior-1-ilo.A heterocyclic radical different from piperazinyl and that has five or six pr ring members and 1-4 heteroatoms per ring, selected from oxygen, nitrogen and sulfur, is such an unsubstituted radical or substituted, for example, pyrrolyl, thienyl, furyl, tetrazol-5-yl which is no substituted or substituted by lower alkyl; thiazol-2-yl which is no substituted or substituted by lower alkoxyphenyl, or morpholino or 4-alkylpiperazin lower-1-yl.
Alquilo inferior R_{1} o R_{2} que es sustituido por tal radical heterocíclico es preferiblemente apropiadamente metilo sustituido, preferiblemente 4-metilpiperazin-1-ilmetilo o morfolinometilo.Lower alkyl R1 or R2 which is substituted by such heterocyclic radical is preferably appropriately substituted methyl, preferably 4-methylpiperazin-1-ylmethyl or morpholinomethyl.
El radical -CH=N-OR_{9} R_{1} o R_{2} se pueden presentar en la configuración trans o cis.The radical -CH = N-OR_ {9} R1 or R2 may be presented in the trans or cis.
Fenilo R_{1} o R_{2} que es sustituido por halógeno, alquilo inferior, trifluorometilo o alcoxi inferior es, por ejemplo, 4-metoxifenilo. R_{1} o R_{2} puede ser solamente fenilo que es sustituido de esta manera si en la fórmula I el símbolo q es 1.Phenyl R 1 or R 2 which is substituted by halogen, lower alkyl, trifluoromethyl or lower alkoxy is, for example, 4-methoxyphenyl. R 1 or R 2 can be only phenyl which is substituted in this way if in the formula I the symbol q is 1.
R_{3} es preferiblemente metilo.R 3 is preferably methyl.
Las sales de los compuestos de fórmula I son sales de adición especialmente ácida con ácidos orgánicos o inorgánicos, especialmente las sales no tóxicas farmacéuticamente aceptables. Los ácidos inorgánicos adecuados son, por ejemplo, ácido carbónico (preferiblemente en la forma de carbonatos o hidrogencarbonatos); ácidos hidrohálicos, tales como ácido clorhídrico; ácido sulfúrico; o ácido fosfórico. Los ácidos orgánicos adecuados son, por ejemplo, ácidos carboxílico, fosfónico, sulfónico o sulfámico, por ejemplo ácido acético, ácido propiónico, ácido octanóico, ácido decanóico, ácido dodecanóico, ácido glicólico, ácido láctico, ácido 2-hidroxibutítico, ácido glucónico, ácido glucosomonocarboxílico, ácido fumárico, ácido succínico, ácido adípico, ácido pimélico, ácido subérico, ácido azeláico, ácido málico, ácido tartárico, ácido cítrico, ácido glucárico, ácido galactárico, amino ácidos, tales como ácido glutámico, ácido aspártico, N-metilglicina, ácido acetilaminoacético, N-acetilasparagina o N-acetilcistina, ácido pirúvico, ácido acetoacético, fosfoserina, ácido 2- o 3- glicerofosfórico, ácido glucoso-6-fosfórico, ácido glucoso-1-fosfórico, fructosa- ácido 1,6-bisfosfórico, ácido maléico, ácido hidroximaléico, ácido metilmaléico, ácido ciclohexanocarboxílico, ácido adamantanocarboxílico, ácido benzoico, ácido salicílico, ácido 1- o 3-hidroxinafil-2-carboxílico, ácido 3,4,5-trimetoxibenzoico, ácido 2-fenoxibenzoico, ácido 2-acetoxibenzoico, ácido 4-aminosalicílico, ácido ftálico, ácido fenilacético, ácido mandélico, ácido cinámico, ácido nicotínico, ácido isonicotínico, ácido glucurónico, ácido galacturónico, ácido metano- o etano-sulfónico, ácido 2-hidroxietanosulfónico, ácido etano-1,2-disulfónico, ácido bencenosulfónico, ácido 2-naftalenosulfónico, ácido 1,5-naftalenodisulfónico, ácido 2-, 3- o 4-metilbencenosulfónico, ácido metilsulfúrico, ácido etilsulfúrico, ácido dodecilsulfúrico, ácido N-ciclohexilsulfámico, ácido N-metil-, N-etil-, o N-propil-sulfámico, u otros ácidos protónicos orgánicos, tal como ácido ascórbico.The salts of the compounds of formula I are especially acidic addition salts with organic acids or inorganic, especially pharmaceutically non-toxic salts acceptable. Suitable inorganic acids are, for example, carbonic acid (preferably in the form of carbonates or hydrogencarbonates); hydrochloric acids, such as acid hydrochloric; sulfuric acid; or phosphoric acid. Acids Suitable organic are, for example, carboxylic acids, phosphonic, sulfonic or sulfamic, for example acetic acid, acid propionic, octanoic acid, decanic acid, dodecanoic acid, glycolic acid, lactic acid, acid 2-hydroxybutytic, gluconic acid, acid glycosomonocarboxylic acid, fumaric acid, succinic acid, acid adipic acid, pimelic acid, subic acid, azelic acid, acid Malic acid, tartaric acid, citric acid, glucaric acid, acid galactaric, amino acids, such as glutamic acid, acid aspartic, N-methylglycine, acetylaminoacetic acid, N-acetylasparagine or N-acetylcystine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3- glycerophosphoric acid, acid glucoso-6-phosphoric acid glucoso-1-phosphoric, fructose-acid 1,6-bisphosphoric, maleic acid, acid hydroximaléic, methylmaléic acid, cyclohexanecarboxylic acid, adamantane carboxylic acid, benzoic acid, salicylic acid, acid 1- or 3-hydroxynafil-2-carboxylic acid, 3,4,5-Trimethoxybenzoic acid, acid 2-phenoxybenzoic acid 2-acetoxybenzoic acid 4-aminosalicylic, phthalic acid, acid phenylacetic, mandelic acid, cinnamic acid, nicotinic acid, Isonicotinic acid, glucuronic acid, galacturonic acid, acid methane- or ethane sulfonic acid 2-hydroxyethanesulfonic acid ethane-1,2-disulfonic acid benzenesulfonic acid, 2-naphthalenesulfonic acid, acid 1,5-naphthalenedisulfonic acid 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, acid ethylsulfuric acid, dodecylsulfuric acid, acid N-cyclohexylsulfamic acid N-methyl-, N-ethyl-, or N-propyl sulfamic acid, or other acids Organic protonics, such as ascorbic acid.
Los compuestos de fórmula I que tienen por lo menos un grupo ácido, por ejemplo como un grupo carboxilo libre son capaces de formar sales internas o sales de metal o amonio, tales como sales de metal alcalino o de metal alcalino terreo, por ejemplo, sales de sodio, potasio, magnesio o calcio, o sales de amonio con amonio o aminas orgánicas adecuadas, tales como monoaminas terciarias, por ejemplo trietilamina o tri(2-hidroxietil)amina, o bases heterocíclicas, por ejemplo N-etilpiperidina o N,N'-dimetilpiperazina.The compounds of formula I which have less an acid group, for example as a free carboxyl group are capable of forming internal salts or metal or ammonium salts, such as alkali metal or alkaline earth metal salts, by example, sodium, potassium, magnesium or calcium salts, or salts of ammonium with ammonium or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri (2-hydroxyethyl) amine, or bases heterocyclics, for example N-ethylpiperidine or N, N'-dimethylpiperazine.
Para propósitos de aislamiento o purificación también es posible utilizar sales farmacéuticamente indadecuadas, por ejemplo picratos o percloratos. Solamente las sales que son farmacéuticamente aceptables y no tóxicas (en las dosis apropiadas) se utilizan terapéuticamente y por lo tanto se prefieren estas sales.For isolation or purification purposes it is also possible to use pharmaceutically inappropriate salts, for example picrates or perchlorates. Only the salts that are Pharmaceutically acceptable and non-toxic (in appropriate doses) they are used therapeutically and therefore these are preferred you go out.
En vista de la relación cercana entre los compuestos novedosos en la forma libre y en la forma de sus sales, que incluyen aquellas sales que se pueden utilizar como intermedios, por ejemplo en la purificación o identificación de los compuestos novedosos, anteriormente y posteriormente los compuestos libres se deben entender como significando también las sales correspondientes, según sean apropiadas y convenientes.In view of the close relationship between novel compounds in the free form and in the form of their salts, which include those salts that can be used as intermediates, for example in the purification or identification of the compounds novel, previously and subsequently the free compounds are they must understand how the salts also mean corresponding, as appropriate and convenient.
Los compuestos de la fórmula I tienen propiedades valiosas farmacológicamente útiles. En particular ellas despliegan actividades inhibitorias específicas que son de interés farmacológico. Ellas son efectivas principalmente como inhibidores de la tirosina quinasa de proteína y/o (además) como inhibidores de proteína serina/treonina quinasas; ellas exhiben, por ejemplo, potente inhibición de la actividad de tirosina quinasa del receptor para el factor de crecimiento epidérmico (EGF) y de la c-erbB2 quinasa. Estas actividades de enzima específicas de receptor juegan un papel clave en la transmisión de señal en un gran número de células de mamíferos, incluyendo las células humanas, especialmente las células epiteliales, las células del sistema inmune y las células del sistema nervioso central y periférico. Por ejemplo, en varios tipos de célula, la activación inducida por EGF de la proteína tirosina quinasa asociada al receptor (EGF-R-PTK) es un prerrequisito de la división celular y así para la proliferación de la población de células. Un incremento en el número de los inhibidores de tirosina quinasa específicos del receptor EGF inhibe así la proliferación de las células. La misma aplica análogamente a otra proteína quinasa mencionada anteriormente y posteriormente.The compounds of the formula I have valuable pharmacologically useful properties. Particularly them display specific inhibitory activities that are of interest pharmacological. They are effective primarily as inhibitors of protein tyrosine kinase and / or (in addition) as inhibitors of serine protein / threonine kinases; they exhibit, for example, potent inhibition of receptor tyrosine kinase activity for epidermal growth factor (EGF) and of the c-erbB2 kinase. These enzyme activities specific receiver play a key role in the transmission of signal in a large number of mammalian cells, including human cells, especially epithelial cells, cells of the immune system and the cells of the central nervous system and peripheral. For example, in several cell types, activation EGF-induced tyrosine kinase protein associated with receiver (EGF-R-PTK) is a prerequisite of cell division and thus for the proliferation of The population of cells. An increase in the number of EGF receptor-specific tyrosine kinase inhibitors inhibit thus the proliferation of the cells. It applies analogously to another protein kinase mentioned above and later.
Además o en lugar de inhibir la proteína tirosina quinasa del receptor EGF, los compuestos de fórmula I también inhiben en varias proporciones otra proteínas tirosina quinasas que están involucradas en la transmisión de señal mediada por factores tróficos, por ejemplo la quinasa abl, especialmente la quinasa v-abl, las quinasas provenientes de la familia de las quinasas src, especialmente la quinasa c-src, lck, fyn; otras quinasas de la familia EGF, por ejemplo la quinasa c-erbB2 (HER-2), quinasa c-erbB3, quinasa c-erbB4; los miembros de la familia de la proteína tirosina quinasa del receptor PDGF, por ejemplo la quinasa receptora PDGF, la quinasa receptora CSF-1, el kit de la quinasa receptora, la quinasa receptora VEGF y la quinasa receptora FGF; la quinasa receptora del factor de crecimiento similar a insulina (quinasa IGF-1), y las serina/treonina quinasas, por ejemplo la proteína quinasa C o las quinasas cdc, todas las cuales juegan una parte en la regulación del crecimiento y la transformación de las células de mamífero, incluyendo las células humanas.In addition or instead of inhibiting protein EGF receptor tyrosine kinase, the compounds of formula I they also inhibit another tyrosine protein in several proportions kinases that are involved in mediated signal transmission for trophic factors, for example the abl kinase, especially the v-abl kinase, the kinases from the src kinase family, especially kinase c-src, lck, fyn; other kinases of the EGF family, for example c-erbB2 kinase (HER-2), c-erbB3 kinase, kinase c-erbB4; members of the protein family PDGF receptor tyrosine kinase, for example the receptor kinase PDGF, the CSF-1 receptor kinase, the kit of the receptor kinase, VEGF receptor kinase and receptor kinase FGF; growth factor receptor kinase similar to insulin (IGF-1 kinase), and serine / threonine kinases, for example protein kinase C or cdc kinases, all of which play a part in growth regulation and the transformation of mammalian cells, including human cells
La inhibición de la proteína tirosina quinasa específica del receptor EGF (EGF-R-PTK) se puede demostrar utilizando métodos conocidos, por ejemplo utilizando un dominio intracelular recombinante del receptor EGF (EGF-R ICD; ver, por ejemplo, E. McGlynn et al., Europ. J. Biochem. 207, 265-275 (1992)). Comparado con el control sin inhibidor, los compuestos de fórmula I inhiben la actividad de la enzima en un 50% (IC_{50}), por ejemplo en una concentración de desde 0.0005 a 1 \muM, especialmente de 0.001 a 0.1 \muM.Inhibition of the EGF receptor-specific tyrosine kinase protein (EGF-R-PTK) can be demonstrated using known methods, for example using a recombinant intracellular domain of the EGF receptor (EGF-R ICD; see, for example, E. McGlynn et al ., Europ. J. Biochem. 207, 265-275 (1992)). Compared to the control without inhibitor, the compounds of formula I inhibit the activity of the enzyme by 50% (IC 50), for example at a concentration of from 0.0005 to 1 µM, especially 0.001 to 0.1 µM.
La acción de los compuestos de fórmula I sobre la fosforilación de la tirosina celular estimulada por EGF en el receptor EGF se puede determinar en la línea celular del carcinoma epitelial A431 humano por medio de un ELISA que se describe en U. Trinks et al., J. Med. Chem. 37:7, 1015-1027 (1994). En esta prueba (EGFR-ELISA) los compuestos de fórmula I exhiben un IC_{50} de aproximadamente 0.001 a 1 \muM.The action of the compounds of formula I on phosphorylation of EGF-stimulated cell tyrosine in the EGF receptor can be determined in the human A431 epithelial carcinoma cell line by means of an ELISA described in U. Trinks et al ., J. Med. Chem. 37: 7, 1015-1027 (1994). In this test (EGFR-ELISA) the compounds of formula I exhibit an IC 50 of about 0.001 to 1 µM.
La estimulación de las células BALB/c3T3 quiescentes con EGF inducen rápidamente la expresión de c-fos mARN. El pretratamiento de las células con un compuesto de fórmula I antes de la estimulación con EGF inhibe la expresión del c-fos a un IC_{50} de aproximadamente desde 0.001 a 0.1 \muM. Este procedimiento de prueba es de manera similar descrito en U. Trinks et al., J. Med. Chem. 37:7, 1015-1027 (1994).Stimulation of quiescent BALB / c3T3 cells with EGF rapidly induces c-fos mRNA expression. Pretreatment of the cells with a compound of formula I before stimulation with EGF inhibits c-fos expression at an IC 50 of approximately 0.001 to 0.1 µM. This test procedure is similarly described in U. Trinks et al ., J. Med. Chem. 37: 7, 1015-1027 (1994).
En el rango micromolar también, los compuestos de fórmula I también exhiben, por ejemplo, la inhibición del crecimiento celular de las líneas celulares dependientes de EGF, por ejemplo la línea celular de queratinocito de ratón BALB/c epidermoide (ver Weissmann, B.A. y Aaronson, S.A., Cell 32, 599 (1983)) o la línea celular A431, que son reconocidas como fuentes estándar útiles de las células epiteliales dependientes de EGF (ver Carpenter, G. y Zendegni, J. Anal. Biochem. 153, 279-282 (1985)). En un método de prueba conocido (ver Meyer et al., Int J. Cáncer 43, 851 (1989)), la actividad inhibitoria de los compuestos de fórmula I se determina, brevemente, como sigue: las células BALB/MK (10 000/pozo de placa microtítulo) se transfieren a placas de microtítulo de 96 pozos. Los compuestos de prueba (disueltos en DMSO) se agregaron en una serie de concentraciones (series de dilución) de tal manera que la concentración final del DMSO no es mayor del 1% (v/v). Después de la adición, las placas se incubaron durante tres días durante el cual los cultivos de control sin el compuesto de prueba son capaces de sufrir por lo menos tres ciclos de división celular. El crecimiento de las células MK se mide por medio de un teñido de Metileno Blue: después de la incubación las células se fijan con glutaraldehído, se lavan con agua y se tiñen con 0.05% de Metileno Blue. Después de la etapa de lavado la mancha se eluye con 3% de HCl y la densidad óptica por pozo de la placa de microtítulo se mide utilizando un Titertek Multiscan a 665 nm. Los valores IC_{50} se determinan por medio de un sistema con ayuda de computadora utilizando la fórmula:Also in the micromolar range, the compounds of formula I also exhibit, for example, inhibition of cell growth of EGF-dependent cell lines, for example the BALB / c epidermoid mouse keratinocyte cell line (see Weissmann, BA and Aaronson , SA, Cell 32, 599 (1983)) or the A431 cell line, which are recognized as useful standard sources of EGF-dependent epithelial cells (see Carpenter, G. and Zendegni, J. Anal. Biochem. 153, 279- 282 (1985)). In a known test method (see Meyer et al ., Int J. Cancer 43, 851 (1989)), the inhibitory activity of the compounds of formula I is determined, briefly, as follows: BALB / MK cells (10,000 / microtiter plate well) are transferred to 96 well microtiter plates. Test compounds (dissolved in DMSO) were added in a series of concentrations (dilution series) such that the final concentration of DMSO is not greater than 1% (v / v). After the addition, the plates were incubated for three days during which the control cultures without the test compound are capable of suffering at least three cycles of cell division. The growth of MK cells is measured by means of a dyeing of Methylene Blue: after incubation the cells are fixed with glutaraldehyde, washed with water and stained with 0.05% of Methylene Blue. After the washing step the stain is eluted with 3% HCl and the optical density per well of the microtiter plate is measured using a Titertek Multiscan at 665 nm. The IC 50 values are determined by means of a computer-assisted system using the formula:
IC_{50} = [(OD_{prueba} - OD_{mancha})/(OD_{control} - OD_{mancha})] x 100IC_ {50} = [(OD_ {test} - OD_ {stain}) / (OD_ {control} - OD_ {stain})] x 100
El valor IC_{50} en estos experimentos se da como aquella concentración del compuesto de prueba en cuestión que da como resultado en un conteo de célula que es 50% inferior que aquel obtenido utilizando el control sin inhibidor. Los compuestos de fórmula I despliegan actividad inhibitoria en el rango micromolar, por ejemplo un IC_{50} de aproximadamente desde 0.1 a 1 \muM.The IC50 value in these experiments is given as that concentration of the test compound in question that results in a cell count that is 50% lower than that obtained using the control without inhibitor. The compounds of formula I display inhibitory activity in the range micromolar, for example an IC 50 of about 0.1 to 1 µM.
Los compuestos de fórmula I despliegan inhibición del crecimiento de las células tumorales también in vivo como se muestra, por ejemplo, por la prueba descrita adelante: la prueba está basada en la inhibición del crecimiento del carcinoma epidermoide humano A431 (ATCC No CRL 1555; American Type Culture Collection, Rockville Maryland, USA; ver Santon, J.B. et al., Cancer Research 46, 4701-4705 (1986) y Ozawa, S., et al., Int. J. Cancer 40, 706-710 (1987)), que es trasplantado en ratones desnudos BALB/c hembras (Bomholtgard, Dinamarca). Este carcinoma exhibe un crecimiento que se correlaciona con la extensión de la expresión del receptor EGF. En el experimento, los tumores que tienen un volumen de aproximadamente 1 cm^{3} cultivados in vivo son quirúrgicamente removidos de animales experimentales bajo condicione estériles. Estos tumores son desmenuzados y suspendidos en 10 volúmenes (p/v) de solución salina amortiguada de fosfato. La suspensión se inyecta s.c. (0.2 ml/ratón en solución salina amortiguada de fosfato) en el flanco izquierdo de los animales. Alternativamente, 1 x 10^{6} células provenientes de un cultivo in vitro en 0.2 ml de solución salina amortiguada de fosfato se puede inyectar. El tratamiento con los compuestos de prueba de la fórmula I se inicia a los 5 o 7 días después del trasplante, cuando los tumores han alcanzado un diámetro de 4-5 mm. El compuesto activo en cuestión se administra (en diferentes dosis para diferentes grupos de animales) una vez al día durante 15 días sucesivos. El crecimiento tumoral se determina al medir el diámetro de los tumores a lo largo de los tres ejes que están perpendiculares uno al otro. Los volúmenes del tumor se calculan utilizando la fórmula conocida p x L x D^{2}/g (ver Evans B.D., et al., Brit. J. Cancer 45, 466-8 (1982)). Los resultados se dan en porcentajes de tratamiento/control (T/C x 100 = T/C %). A una dosis de 3 a 50 mg/kg del ingrediente activo, diferente inhibición del crecimiento tumoral se encuentra, por ejemplo los valores T/C % de menos de 10, que indican fuerte inhibición del crecimiento tumoral.Compounds of formula I display growth inhibition of tumor cells also in vivo as shown, for example, by the test described below: the test is based on the inhibition of the growth of human epidermoid carcinoma A431 (ATCC No CRL 1555; American Type Culture Collection, Rockville Maryland, USA; see Santon, JB et al ., Cancer Research 46, 4701-4705 (1986) and Ozawa, S., et al ., Int. J. Cancer 40, 706-710 (1987) ), which is transplanted in female BALB / c nude mice (Bomholtgard, Denmark). This carcinoma exhibits growth that correlates with the extent of EGF receptor expression. In the experiment, tumors that have a volume of approximately 1 cm 3 cultured in vivo are surgically removed from experimental animals under sterile conditions. These tumors are shredded and suspended in 10 volumes (w / v) phosphate buffered saline. The suspension is injected sc (0.2 ml / mouse in phosphate buffered saline) in the left flank of the animals. Alternatively, 1 x 10 6 cells from an in vitro culture in 0.2 ml of phosphate buffered saline can be injected. Treatment with the test compounds of formula I begins 5 or 7 days after transplantation, when the tumors have reached a diameter of 4-5 mm. The active compound in question is administered (in different doses for different groups of animals) once a day for 15 successive days. Tumor growth is determined by measuring the diameter of the tumors along the three axes that are perpendicular to each other. Tumor volumes are calculated using the known formula px L x D 2 / g (see Evans BD, et al ., Brit. J. Cancer 45, 466-8 (1982)). The results are given in treatment / control percentages (T / C x 100 = T / C%). At a dose of 3 to 50 mg / kg of the active ingredient, different inhibition of tumor growth is found, for example T / C% values of less than 10, which indicate strong inhibition of tumor growth.
También o en lugar de inhibir la proteína de tirosina quinasa del receptor EGF, los compuestos de fórmula I también inhiben otras proteínas de tirosina quinasa que están involucradas en la transmisión de señal mediada por factores tróficos, por ejemplo quinasa abl, tal como especialmente quinasa v-abl (IC_{50} por ejemplo de 0.01 a 5 \muM), las quinasas provenientes de la familia de las quinasas src, tales como especialmente la quinasa c-src (IC_{50} por ejemplo de 0.1 a 10 \muM), y quinasa c-erbB2 (HER-2), y la serina/treonina quinasa, por ejemplo la proteína quinasa C, todas las cuales están involucradas en la regulación y la transformación del crecimiento en las células de mamíferos, incluyendo las células humanas.Also or instead of inhibiting protein from EGF receptor tyrosine kinase, the compounds of formula I they also inhibit other tyrosine kinase proteins that are involved in factor-mediated signal transmission trophic, for example abl kinase, such as especially kinase v-abl (IC 50 for example from 0.01 to 5 µM), kinases from the src kinase family, such as especially c-src kinase (IC 50 per example from 0.1 to 10 µM), and c-erbB2 kinase (HER-2), and serine / threonine kinase, for example protein kinase C, all of which are involved in the regulation and growth transformation in the cells of mammals, including human cells.
La inhibición anteriormente mencionada de la tirosina quinasa v-abl se determinó mediante los métodos de N. Lydon et al., Oncogene Research 5, 161-173 (1990) y J.F. Geissler et al., Cancer Research 52, 4492-4498 (1992). En estos métodos la [Val^{5}]-angiotensina II y la [\gamma^{-32}P]-ATP se utilizan como sustratos.The above-mentioned inhibition of tyrosine kinase v-abl was determined by the methods of N. Lydon et al ., Oncogene Research 5, 161-173 (1990) and JF Geissler et al ., Cancer Research 52, 4492-4498 (1992 ). In these methods, [Val 5] - angiotensin II and [γ-32 P] -ATP are used as substrates.
La inhibición de la tirosina quinasa c-erbB2 (HER-2) se puede determinar, por ejemplo, análogamente al método utilizado por EGF-R-TPK (ver C. House et al., Europ. J. Biochem. 140, 363-367 (1984)). La quinasa c-erbB2 se puede aislar, y su actividad determinar, por medio de protocolos conocidos per se, por ejemplo de acuerdo con T. Akiyama et al., Science 232, 1644 (1986).The inhibition of tyrosine kinase c-erbB2 (HER-2) can be determined, for example, analogously to the method used by EGF-R-TPK (see C. House et al ., Europ. J. Biochem. 140, 363- 367 (1984)). The c-erbB2 kinase can be isolated, and its activity determined, by means of protocols known per se , for example according to T. Akiyama et al ., Science 232, 1644 (1986).
Los compuestos de la fórmula I que inhiben la actividad de la tirosina quinasa del receptor del factor de crecimiento epidérmico (EGF) o adicionalmente de otras proteínas tirosina quinasas mencionadas son por lo tanto útiles, por ejemplo, en el tratamiento de tumores benignos o malignos. Ellos son capaces de efectuar regresión tumoral y de evitar la formación de metástasis de tumor y de crecimiento de metástasis. Ellos se pueden utilizar especialmente en el caso de hiperproliferación epidérmica (soriasis), en el tratamiento de neoplasias de carácter epitelial, por ejemplo, carcinomas mamarios, y en leucemias. Además, los compuestos de la fórmula I (especialmente los compuestos novedosos) se pueden utilizar en el tratamiento de aquellos padecimientos del sistema inmune en el cual varios o, especialmente, las proteínas tirosina quinasas individuales y/o (adicionalmente más) la proteína serina/treonina quinasas está involucrada; estos compuestos de la fórmula I también se puede utilizar en el tratamiento de aquellos padecimientos del sistema nervioso central o periférico en el cual la transmisión de señal por varias o, especialmente, una proteína tirosina quinasa simple y/o (adicionalmente) la proteína serina/treonina quinasas está involucrada.Compounds of formula I that inhibit receptor tyrosine kinase activity factor epidermal growth (EGF) or additionally of other proteins Tyrosine kinases mentioned are therefore useful, for example, in the treatment of benign or malignant tumors. They are capable to perform tumor regression and avoid the formation of Tumor metastasis and metastasis growth. They can use especially in the case of epidermal hyperproliferation (psoriasis), in the treatment of epithelial neoplasms, for example, mammary carcinomas, and in leukemias. In addition, the compounds of the formula I (especially the novel compounds) can be used in the treatment of those conditions of immune system in which several or, especially, proteins individual tyrosine kinases and / or (additionally more) protein serine / threonine kinases is involved; these compounds of the formula I can also be used in the treatment of those central or peripheral nervous system conditions in which signal transmission by several or, especially, a protein simple tyrosine kinase and / or (additionally) protein Serine / threonine kinases are involved.
En general, la presente invención se relaciona también con el uso de compuestos de la fórmula I para la inhibición de la proteína quinasas mencionadas.In general, the present invention relates to also with the use of compounds of the formula I for inhibition of the protein kinases mentioned.
Los compuestos de acuerdo con la invención se pueden utilizar tanto solos como en combinación con otros compuestos farmacológicamente activos, por ejemplo junto con inhibidores de las enzimas de síntesis de poliamina, inhibidores de la proteína quinasa C, inhibidores de otras tirosina quinasas, citoquinas, reguladores del crecimiento negativo, por ejemplo, TGF-\beta o IFN-\beta, inhibidores de aromatasa, agentes antiestrógenos y/o citoestáticos.The compounds according to the invention are they can use both alone and in combination with other compounds pharmacologically active, for example together with inhibitors of polyamine synthesis enzymes, protein inhibitors kinase C, other tyrosine kinase inhibitors, cytokines, negative growth regulators, for example, TGF-? Or IFN-?, aromatase inhibitors, antiestrogen agents and / or cytostatics
En los objetos preferidos de la invención mencionados posteriormente, las definiciones generales se pueden reemplazar por las definiciones más específicas dadas al inicio, donde es apropiado y conveniente.In the preferred objects of the invention mentioned below, the general definitions can be replace with the more specific definitions given at the beginning, where it is appropriate and convenient.
Los compuestos más preferidos de la fórmula I son aquellos descritos en los Ejemplos y sus sales farmacéuticamente aceptables.The most preferred compounds of the formula I are those described in the Examples and their pharmaceutically salts acceptable.
Los compuestos de fórmula I y sus sales se preparan mediante procesos conocidos per se. El proceso de acuerdo con la invención comprendeThe compounds of formula I and their salts are prepared by processes known per se . The process according to the invention comprises
- a)to)
- hacer reaccionar un derivado de pirrolo[2,3-d]pirimidina de la fórmula IVdo react a derivative of pyrrolo [2,3-d] pyrimidine of the formula IV
- en la cual X es un grupo saliente adecuado, Z es hidrógeno o 1-aril-alquilo inferior y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en los radicales R_{1} y R_{2} si es necesario están protegidos por grupos protectores, con un derivado de anilina de la fórmula Vin which X is a suitable leaving group, Z is hydrogen or 1-aryl-lower alkyl and the others substituents are as defined above for the compounds of formula I, the free functional groups present in the radicals R 1 and R 2 if necessary are protected by protecting groups, with an aniline derivative of the formula V
- en la cual R, R_{3} n y q son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores fácilmente removibles, y grupos protectores que se remueven y, si está presente, el radical 1-aril-alquilo inferior Z, oin which R, R 3 n and q are as defined above for the compounds of formula I, the free functional groups present in the radical R if necessary they are easily protected by protective groups removable, and protective groups that are removed and, if present, the 1-aryl-alkyl radical lower Z, or
- b)b)
- hacer reaccionar un derivado de pirrolo[2,3-d]pirimidin-4-ona de la fórmula VIdo react a derivative of pyrrolo [2,3-d] pyrimidin-4-one of formula VI
- en la cual Z' es 1-aril-alquilo inferior y R_{1} y R_{2} son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en los radicales R_{1} y R_{2} si es necesario están protegidos por grupos protectores fácilmente removibles, en la presencia de un agente deshidratante y una amina terciaria, con una fenilamina de la fórmula V anterior y remover los grupos protectores presentes, oin which Z 'is 1-aryl-lower alkyl and R 1 and R2 are as defined above for the compounds of formula I, the free functional groups present in the radicals R_ {1} and R2_ if necessary are protected by groups easily removable protectors, in the presence of an agent dehydrating and a tertiary amine, with a phenylamine of the formula V above and remove the protecting groups present, or
- e)and)
- para la preparación de un compuesto de fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula -CH=N-OR_{9} en el cual R_{9} es hidrógeno o alquilo inferior, y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es formilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con un derivado de hidroxilamina de la fórmula VIIIfor the preparation of a compound of formula I in which one of the radicals R1 and R2 is a radical of the formula -CH = N-OR9 in which R9 is hydrogen or lower alkyl, and the other substituents are as defined above for the compounds of formula I, reacting a compound of formula I, in which one of the radicals R1 and R2 is formyl and the other substituents are as defined. above for the compounds of formula I, the groups functional functions present in the radical R if necessary are protected by protecting groups, with a hydroxylamine derivative of formula VIII
(VIII)H_{2}N-O-R_{12}(VIII) H 2 N-O-R 12
- en la cual R_{12} es hidrógeno o alquilo inferior, y grupos protectores removibles presentes, oin which R 12 is hydrogen or lower alkyl, and protecting groups removable present, or
- f)F)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es piperidina-1-carbonilo, piperazina-1-carbonilo, 4-alquilpiperazina inferior-1-carbonilo o moforlino-4-carbonilo, y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es carboxilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, o un derivado de ácido carboxílico reactivo de tal compuesto, con una amina de la fórmula VIIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is piperidine-1-carbonyl, piperazine-1-carbonyl, 4-alkylpiperazine lower-1-carbonyl or moforlino-4-carbonyl, and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is carboxyl and the others substituents are as defined above for the compounds of formula I, the free functional groups present in the radical R if necessary they are protected by protective groups, or a derivative of reactive carboxylic acid of such compound, with a amine of formula VII
(VII)HN(R_{10})R_{11}(VII) HN (R 10) R 11
- en la cual los radicales R_{10} y R_{11} juntos son pentano-1,5-diilo, 3-azapentano-1,3-diilo, 3-N-alquilo inferior-3-azapentano-1,3-diilo o 3-oxapentano-1,3-diilo, y luego remover los grupos protectores presentes, oin which the radicals R 10 and R 11 together are pentane-1,5-diyl, 3-azapentane-1,3-diyl, 3-N-alkyl lower-3-azapentane-1,3-diyl or 3-oxapentane-1,3-diyl, and then remove the protective groups present, or
- g)g)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es tiocarbamoilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es aminocarbonilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos mediante grupos protectores, con el reactivo de Lawesson, y luego remover los grupos protectores presentes, ofor the preparation of a compound of the formula I in which one of the radicals R 1 and R 2 is thiocarbamoyl and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R 1 and R 2 is aminocarbonyl and the Other substituents are as defined above for compounds of formula I, the free functional groups present in the radical R if necessary are protected by groups protectors, with Lawesson's reagent, and then remove the protective groups present, or
- h)h)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es R_{13}-tiazol-2-ilo en el cual R_{13} en cada caso es alquilo o fenilo inferior no sustituido o sustituido y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es tiocarbamoilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos mediante grupos protectores, con un compuesto de la fórmula IXfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is R 13 -thiazol-2-yl in which R 13 in each case is lower alkyl or phenyl not substituted or substituted and the other substituents are as defined above for the compounds of formula I, making reacting a compound of formula I, in which one of the radicals R 1 and R 2 is thiocarbamoyl and the others substituents are as defined above for the compounds of formula I, the free functional groups present in the radical R if necessary they are protected by protective groups, with a compound of formula IX
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- en la cual X es un grupo saliente y R_{13} en cada caso es alquilo o fenilo inferior no sustituido o sustituido, grupos funcionales libres presentes en el radical R_{13} si es necesario están protegidos por grupos protectores, y luego grupos protectores que se remueven presentes, oin which X is a leaving group and R 13 in each case is alkyl or phenyl lower unsubstituted or substituted, free functional groups present in the radical R_ {13} if necessary are protected by protective groups, and then protective groups that are removed present, or
- i)i)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es tetrazol-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es ciano y los otros sustituyentes son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con una acida de metal alcalino adecuada, y luego remover los grupos protectores presentes, ofor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is tetrazol-5-yl and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is cyano and the others substituents are as defined above for the compounds of the formula I, the free functional groups present in the radical R if necessary are protected by protective groups, with a suitable alkali metal acid, and then remove the protective groups present, or
- j)j)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es 2-alquiltetrazol inferior-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es tretrazol-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con el yoduro de alquilo inferior apropiado, y luego remover los grupos protectores presentes, ofor the preparation of a compound of the formula I in which one of the radicals R 1 and R 2 is 2-alkyltetrazole lower-5-ilo and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is tretrazol-5-yl and the others substituents are as defined above for the compounds of the formula I, the free functional groups present in the radical R if necessary are protected by protective groups, with the appropriate lower alkyl iodide, and then remove the protective groups present, or
\newpage\ newpage
- k)k)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en el cual por lo menos un radical R_{4} es alquilsulfonilamino inferior, bencenosulfonilamino o toluenosulfonilamino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario están protegidos por grupos protectores, con un compuesto de fórmula Xin which by at least one radical R 4 is lower alkylsulfonylamino, benzenesulfonylamino or toluenesulfonylamino and the others Substituents and symbols are as defined above for the compounds of formula I, reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in which at least one radical R 4 is amino and the other substituents and symbols are as defined above for the compounds of the formula I, the groups functional functions present in the radical R and, if present, the other radicals R_ {4} if necessary are protected by protecting groups, with a compound of formula X
(X)R_{14}-SO_{2}-X(X) R 14 -SO 2 -X
- en el cual X es cloro o bromo y R_{14} es alquilo inferior, fenilo o 4-metilfenilo, y luego remover los grupos protectores presentes, oin which X is chlorine or bromine and R 14 is lower alkyl, phenyl or 4-methylphenyl, and then remove the groups protectors present, or
- l)l)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en el cual por lo menos un radical R_{4} es un radical de la fórmula -N=C(R_{5})-R_{6} en el cual R_{5} es hidrógeno y R_{6} es como se definió anteriormente para los compuestos de la fórmula I y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario están protegidos por grupos protectores, con un acetal de la fórmula XIin which by at least one radical R4 is a radical of the formula -N = C (R 5) - R 6 in which R 5 is hydrogen and R 6 is as defined above for the compounds of the formula I and the other substituents and symbols are as defined above for the compounds of formula I, by reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in the which at least one radical R4 is amino and the others Substituents and symbols are as defined above for the compounds of formula I, the free functional groups present in the radical R and, if present, the other radicals R4 if necessary they are protected by protective groups, with a acetal of formula XI
- en la cual R_{15} y R_{16} son cada uno individualmente alquilo inferior o juntos pentano-1,5-diilo, 3-N-alquilo inferior-3-azapentano-1,5-diilo o 3-oxapentano-1,5-diilo, y R_{17} es alquilo inferior, y luego remover los grupos protectores presentes, oin which R 15 and R 16 are each individually lower alkyl or together pentane-1,5-diyl, 3-N-alkyl lower-3-azapentane-1,5-diyl or 3-oxapentane-1,5-diyl, and R 17 is lower alkyl, and then remove the groups protectors present, or
- m)m)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en el cual por lo menos un radical R_{4} es N^{3}-alquilureido inferior o N^{3}-fenilureido y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario están protegidos por grupos protectores, con un isocianato de la fórmula XIIin which by at least one radical R 4 is N 3 -alkylureido lower or N3 -phenylureido and the others Substituents and symbols are as defined above for the compounds of formula I, reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in which at least one radical R 4 is amino and the other substituents and symbols are as defined above for the compounds of the formula I, the groups functional functions present in the radical R and, if present, the other radicals R_ {4} if necessary are protected by protecting groups, with an isocyanate of formula XII
(XII)R_{18}-N=C=O(XII) R 18 -N = C = O
- en el cual R_{18} es alquilo o fenilo inferior, y luego remover los grupos protectores presentes, oin which R 18 is lower alkyl or phenyl, and then remove the groups protectors present, or
- n)n)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en el cual por lo menos un radical R_{4} es N^{3}-alquiltioureido inferior o N^{3}-feniltioureido y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario están protegidos por grupos protectores, con un isotiocianato de la fórmula XIIIin which by at least one radical R_ {4} is N 3 -alkylthioureido lower or N3 -phenylthioureido and the other substituents and Symbols are as defined above for compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is a radical of formula II in which at least one radical R 4 is amino and the Other substituents and symbols are as defined above. for the compounds of the formula I, the free functional groups present in the radical R and, if present, the others radicals R_ {4} if necessary are protected by groups protectors, with an isothiocyanate of the formula XIII
(XIII)R_{18}-N=C=S(XIII) R_ {18} -N = C = S
- en la cual R_{18} es alquilo o fenilo inferior, y luego remover los grupos protectores presentes, oin which R 18 is lower alkyl or phenyl, and then remove the groups protectors present, or
- o)or)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en la cual por lo menos un radical R_{4} es alcoxicarbonilamino inferior o benziloxicarbonilamino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario están protegidos por grupos protectores, con un éster de ácido clorofórmico de la fórmula XIVin which by at least one radical R 4 is lower alkoxycarbonylamino or benzyloxycarbonylamino and the other substituents and symbols are as defined above for the compounds of formula I, by reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in the which at least one radical R4 is amino and the others Substituents and symbols are as defined above for the compounds of formula I, the free functional groups present in the radical R and, if present, the other radicals R4 if necessary they are protected by protective groups, with a chloroformic acid ester of formula XIV
(XIV)Cl-C(=O)- OR_{18}(XIV) Cl-C (= O) - OR_ {18}
- en el cual R_{18} es alquilo o bencilo inferior, y luego remover los grupos protectores presentes, oin which R 18 is alkyl or lower benzyl, and then remove the groups protectors present, or
y después llevar a cabo una de las variantes del proceso a) a o), si es necesario para la preparación de una sal, convirtiendo un compuesto libre de la fórmula I obtenido en una sal o, si es necesario para la preparación de un compuesto libre, convirtiendo una sal de un compuesto de la fórmula I obtenido en el compuesto libre,and then carry out one of the variants of the process a) to o), if necessary for the preparation of a salt, converting a free compound of the formula I obtained into a salt or, if necessary for the preparation of a free compound, converting a salt of a compound of the formula I obtained in the free compound,
en donde el prefijo "inferior" denota un radical que tiene hasta y que incluye un máximo de 7 átomos de carbono.where the "lower" prefix denotes a radical that has up to and that includes a maximum of 7 atoms of carbon.
Los procesos anteriores se describen en detalle adelante (ver también German Offenlegungsschrift No. 30 36 390, publicado en mayo 13 1982, y A. Jorgensen et al., J. Heterocycl. Chem. 22, 859 [1985]). En la descripción más precisa que sigue, a menos que se indique otra cosa, los radicales R, R_{1} y R_{2} y n son como se definieron para los compuestos de la fórmula I.The above processes are described in detail below (see also German Offenlegungsschrift No. 30 36 390, published May 13 1982, and A. Jorgensen et al ., J. Heterocycl. Chem. 22, 859 [1985]). In the most precise description that follows, unless otherwise indicated, the radicals R, R1 and R2 and n are as defined for the compounds of the formula I.
Los productos finales de la fórmula I pueden contener sustituyentes que también se pueden utilizar como grupos protectores en los materiales de partida para la preparación de otros productos finales de la fórmula I. A menos que el contexto indique otra cosa, el término "grupo protector" se utiliza en el texto para denotar solamente un grupo fácilmente removible que no es constituyente del producto final deseado particular de la fórmula I.The final products of formula I can contain substituents that can also be used as groups protectors in the starting materials for the preparation of other final products of formula I. Unless the context indicate otherwise, the term "protective group" is used in the text to denote only an easily removable group that is not constituent of the particular desired end product of the formula I.
Proceso a)Process to)
En el compuesto de la fórmula IV un grupo saliente adecuado X es preferiblemente halógeno, tal como bromo, yodo o especialmente cloro. 1-Aril-alquilo inferior Z es preferiblemente 1-fenil-alquilo inferior, tal como especialmente 1-feniletilo o, en particular, bencilo.In the compound of formula IV a group suitable projection X is preferably halogen, such as bromine, iodine or especially chlorine. 1-Aryl-lower alkyl Z is preferably 1-phenyl-alkyl lower, such as especially 1-phenylethyl or, in Particularly benzyl.
Los grupos funcionales libres presentes en los radicales R_{1} y R_{2}, que si es necesario están protegidos por grupos protectores fácilmente removibles, son especialmente amino o alquilamino inferior.The free functional groups present in the radicals R_ {1} and R2_, which if necessary are protected by easily removable protective groups, they are especially amino or lower alkylamino.
Los grupos protectores y su introducción y remoción se describen, por ejemplo, en "Protective Groups in Organic Chemistry", Plenum Press, Londres, New York 1973, y en "Methoden der organischen Chemile", Houben-Weyl, 4ta Edición, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974 y en Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981. Esta es una característica de los grupos protectores que se pueden remover fácilmente, es decir, sin que tengan lugar reacciones secundarias no deseadas, por ejemplo por solvólisis, reducción, fotólisis o alternativamente bajo condiciones fisiológicas.The protective groups and their introduction and removal are described, for example, in "Protective Groups in Organic Chemistry ", Plenum Press, London, New York 1973, and in "Methoden der organischen Chemile", Houben-Weyl, 4th Edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene, "Protective Groups in Organic Synthesis ", John Wiley & Sons, New York 1981. This is a characteristic of the protective groups that can be removed easily, that is, without secondary reactions taking place desired, for example by sololysis, reduction, photolysis or alternatively under physiological conditions.
Un grupo amino protegido puede estar presente, por ejemplo, en forma de un acilamino fácilmente dividible, arilmetilamino, mercaptoamino eterificado o un grupo 2-acil-alqu inferior-1-enilamino.A protected amino group may be present, for example, in the form of an easily divisible acylamino, arylmethylamino, etherified mercaptoamine or a group 2-acyl-alkyl lower-1-enylamino.
En un grupo acilamino correspondiente, acilo es, por ejemplo, el radical acilo de un ácido carboxílico orgánico que tiene, por ejemplo, hasta 18 átomos de carbono, especialmente uno no sustituido o sustituid, por ejemplo halo o arilo sustituido, ácido alcanocarboxílico o uno no sustituido o sustituido, por ejemplo, sustituido por halo-, alcoxi inferior- o nitro-, ácido benzoico, o de un hemiéster de ácido carbónico. Tales grupos acilo son, por ejemplo, alcanoilo inferior, tal como formilo, acetilo o propionilo, halo-alcanoilo inferior, tal como 2-haloacetilo, especialmente 2-cloro, 2-bromo, 2-yodo, 2,2,2-trifluoro, o 2,2,2-tricloroacetilo, no sustituido o sustituido, por ejemplo, sustituido por halo, alcoxi inferior, o nitro, benzoilo, por ejemplo benzoilo, 4-clorobenzoilo, 4-metoxibenzoilo o 4-nitrobenzoilo, o alcoxicarbonilo inferior que es ramificado en la posición 1 del radical alquilo inferior o sustituido adecuadamente en la posición 1 o 2, especialmente terc-alcoxicarbonilo inferior, por ejemplo terc-butoxicarbonilo, arilmetoxicarbonilo que tiene uno o dos radicales arilo que son preferiblemente fenilo que es no sustituido o mono o poli sustituido, por ejemplo, por alquilo inferior, especialmente terc-alquilo inferior, tal como terc-butilo, alcoxi inferior, tal como mertoxi, hidroxilo, halógeno, por ejemplo cloro, y/o por nitro, tal como benziloxicarbonilo no sustituido o sustituido, por ejemplo 4-nitrobenziloxicarbonilo, o difenilmetoxicarbonilo sustituido, por ejemplo benzhidriloxicarbonilo o di(4-metoxifenil)metoxicarbonilo, aroilmetoxicarbonilo en el cual el grupo aroilo es preferiblemente benzoilo que es no sustituido o sustituido, por ejemplo, por halógeno, tal como bromo, por ejemplo fenaciloxicarbonilo, 2-halo-alcoxicarbonilo inferior, por ejemplo, 2,2,2-tricloroetoxicarbonilo, 2-bromoetoxicarbonilo o 2-yodoetoxicarbonilo, o 2-(tri-sililo sustituido)etoxicarbonilo en el cual los sustituyentes son cada uno independientemente de los otros uno no sustituido o sustituido, por ejemplo un radical hidrocarburo alifático, aralifático, cicloalifático o aromático sustituido por alquilo inferior, alcoxi inferior, arilo, halo, o nitro, que tiene hasta 15 átomos de carbono, tal como el correspondiente alquilo inferior no sustituido o sustituido, fenilo-alquilo inferior, cicloalquilo o fenilo, por ejemplo 2-tri-alquilsililetoxicarbonilo inferior, tal como 2-trimetilsililetoxicarbonilo o 2-(di-n-butilmetilsilil)etoxicarbonilo, 2-triarilsililetoxicarbonilo, tal como 2-trifenilsililetoxicarbonilo.In a corresponding acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid that it has, for example, up to 18 carbon atoms, especially one not substituted or substituted, for example halo or substituted aryl, acid alkanocarboxylic or unsubstituted or substituted one, for example, substituted by halo-, lower alkoxy- or nitro-, benzoic acid, or of a carbonic acid hemiester. Such acyl groups are, by eg, lower alkanoyl, such as formyl, acetyl or propionyl, lower halo-alkanoyl, such as 2-haloacetyl, especially 2-chlorine, 2-bromine, 2-iodine, 2,2,2-trifluoro, or 2,2,2-trichloroacetyl, unsubstituted or substituted, for example, substituted by halo, lower alkoxy, or nitro, benzoyl, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl which is branched at position 1 of the lower alkyl radical or suitably substituted in position 1 or 2, especially lower tert-alkoxycarbonyl, for example tert-butoxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals that are preferably phenyl which is unsubstituted or mono or poly substituted, for example, by lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower alkoxy, such as mertoxy, hydroxyl, halogen, for example chlorine, and / or nitro, such as unsubstituted or substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl substituted, for example benzhydryloxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl in which the aroyl group is preferably benzoyl which is unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example, 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (tri-silyl substituted) ethoxycarbonyl in which the substituents are each independently of the other one unsubstituted or substituted, for example a radical aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon substituted by lower alkyl, lower alkoxy, aryl, halo, or nitro, which has up to 15 carbon atoms, such as the corresponding unsubstituted or substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, by example 2-tri-alkylsilylethoxycarbonyl lower, such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl, 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.
En un grupo arilmetilamino, que es un grupo mono, di, o especialmente tri-arilmetilamino, los radicales arilo son especialmente radicales fenilo no sustituidos o sustituidos. Tales grupos son, por ejemplo, benzil-, difenilmetil- y especialmente tritil-amin.In an arylmethylamino group, which is a group mono, di, or especially tri-arylmethylamino, the aryl radicals are especially unsubstituted phenyl radicals or replaced. Such groups are, for example, benzyl-, diphenylmethyl- and especially tritil-amin.
Un grupo mercapto eterificado en un grupo amino protegido por tal radical es especialmente ariltio o aril-alquiltio inferior, en el cual el arilo es, especialmente, fenilo que es no sustituido o sustituido, por ejemplo, por alquilo inferior, tal como metilo o terc-butilo, alcoxi inferior, tal como metoxi, halógeno, tal como cloro, y/o por nitro. Un grupo protector amino correspondiente es, por ejemplo, 4-nitrofeniltio.A mercapto group etherified in an amino group protected by such a radical is especially arylthio or aryl-lower alkylthio, in which the aryl is, especially, phenyl which is unsubstituted or substituted, by example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro. An amino protecting group corresponding is for example 4-nitrophenylthio.
En un radical 2-acil-alqu inferior-1-en-1-ilo que se puede utilizar como un grupo protector amino, el acilo es, por ejemplo, el radical correspondiente de un ácido alcanocarboxílico inferior, de un ácido benzoico que es no sustituido o sustituido, por ejemplo, por alquilo inferior, tal como metilo o ter-butilo, alcoxi inferior, tal como metoxi, halógeno, tal como cloro, y/o por nitro, o especialmente de un hemiéster de ácido carbónico, tal como hemiéster de alquilo inferior de ácido carbónico. Los correspondientes grupos protectores son especialmente 1-alcanoilprop inferior-1-en-2-ilo, tal como 1-acetilprop-1-en-2-ilo, o 1-alcoxicarbonilprop inferior-1-en-2-ilo, por ejemplo 1-etoxicarbonilprop-1-en-2-ilo.In a radical 2-acyl-alkyl lower-1-in-1-yl which can be used as an amino protecting group, the acyl is, for example, the corresponding radical of an acid lower alkanocarboxylic acid, of a benzoic acid that is not substituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro, or especially of a carbonic acid hemiester, such as alkyl hemiester lower carbonic acid. The corresponding protecting groups they are especially 1-alkanoylprop lower-1-in-2-yl, such as 1-acetylprop-1-en-2-yl, or 1-alkoxycarbonylprop lower-1-in-2-yl, for example 1-ethoxycarbonylprop-1-en-2-yl.
Los grupos protectores amino preferidos son radicales acilo de hemiésteres de ácido carbónico, especialmente terc-butiloxicarbonilo, benziloxicarbonilo, que es no sustituido o sustituido, por ejemplo como se indicó, por ejemplo 4-nitrobenziloxicarbonilo, o difenilmetoxicarbonilo, o 2-halo-alcoxicarbonilo inferior, tal como 2,2,2-tricloroetoxicarbonilo, también tritilo o formilo.Preferred amino protecting groups are acyl radicals of carbonic acid hemiesters, especially tert-butyloxycarbonyl, benzyloxycarbonyl, which is unsubstituted or substituted, for example as indicated, for example 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl.
La reacción entre el derivado de fórmula IV y el derivado de anilina de la fórmula V tiene lugar en disolventes polares inertes adecuados, especialmente alcoholes, por ejemplo alcanoles inferiores, tal como metanol, propanol, isopropanol o especialmente etanol o n-butanol. En algunos casos la adición de un solubilizador, tal como 1,3-dimetil-3,4,5,6-tetrahidro 2(1H)-pirimidinona (DMPU), es ventajoso. La reacción tiene lugar a temperaturas elevadas, por ejemplo en un rango de temperatura de 70 a 150ºC, preferiblemente bajo condiciones de reflujo.The reaction between the derivative of formula IV and the Aniline derivative of formula V takes place in solvents suitable inert polar, especially alcohols, for example lower alkanols, such as methanol, propanol, isopropanol or especially ethanol or n-butanol. In some cases the addition of a solubilizer, such as 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H) -pyrimidinone (DMPU), is advantageous. The reaction takes place at elevated temperatures, for example in a temperature range from 70 to 150 ° C, preferably under conditions of reflux.
Si Z en el compuesto de la fórmula IV es 1-aril-alquilo inferior, este radical es removido del precursor resultante del compuesto de la fórmula I (con Z en lugar del átomo de hidrógeno sobre el nitrógeno). Esto se efectúa, por ejemplo, mediante el tratamiento con ácido protónicos, tales como ácido clorhídrico, ácido fosfórico o ácido polifosfórico, a temperaturas preferidas de 20ºC a 150ºC y donde sea apropiado en la presencia de agua (este es especialmente el método preferido para Z = 1-feniletilo); o preferiblemente por tratamiento con ácido Lewis, especialmente AlCl_{3}, en disolventes aromáticos, especialmente en benceno y/o tolueno, a temperatura elevada, especialmente bajo reflujo [esta es especialmente la variante preferida para Z = bencilo; ver también el proceso análogo en Chem. Pharm. Bull. 39(5), 1152 (1991)].If Z in the compound of formula IV is 1-aryl-lower alkyl, east radical is removed from the precursor resulting from the compound of the formula I (with Z instead of the hydrogen atom on the nitrogen). This is done, for example, by treatment with protonic acid, such as hydrochloric acid, phosphoric acid or polyphosphoric acid, at preferred temperatures of 20 ° C to 150 ° C and where appropriate in the presence of water (this is especially the preferred method for Z = 1-phenylethyl); or preferably by treatment with Lewis acid, especially AlCl 3, in aromatic solvents, especially in benzene and / or toluene, at elevated temperature, especially under reflux [this is especially the preferred variant for Z = benzyl; See also the analogous process in Chem. Pharm. Bull. 39 (5), 1152 (1991)].
La remoción de los grupos protectores que no son constituyentes del producto final deseado de la fórmula I se efectúa de manera conocida per se, por ejemplo por medio de solvólisis, especialmente hidrólisis, alcohólisis o acidólisis, o por medio de reducción, especialmente hidrogenólisis o reducción química, donde es apropiado paso a paso o simultáneamente.The removal of the protecting groups that are not constituents of the desired final product of the formula I is carried out in a manner known per se , for example by means of solvolysis, especially hydrolysis, alcohololysis or acidolysis, or by reduction, especially hydrogenolysis or reduction. chemistry, where it is appropriate step by step or simultaneously.
Un grupo amino protegido se libera de manera conocida per se y, de acuerdo con la naturaleza de los grupos protegidos, de varias maneras, preferiblemente por solvólisis o reducción. 2-Halo-alcoxicarbonilamino inferior (donde es apropiado después de la conversión de un grupo 2-bromo-alcoxicarbonilamino inferior en un grupo 2-yodo-alcoxicarbonilamino inferior), aroilmetoxicarbonilamino o 4-nitrobenziloxicarbonilamino se pueden dividir, por ejemplo, mediante tratamiento con un agente reductor químico adecuado, tal como zinc en la presencia de un ácido carboxílico adecuado, tal como ácido acético acuoso. El aroilmetoxicarbonilamino se puede dividir también mediante el tratamiento con un reactivo nucleofílico, preferiblemente formador de sal, tal como tiofenolato de sodio, y 4-nitrobenziloxicarbonilamino también mediante tratamiento con un ditionito de metal alcalino, por ejemplo, ditionito de sodio. El difenilmetoxicarbonilamino no sustituido o sustituido, terc-alcoxicarbonilamino inferior o 2-sililetoxicrbonilamino trisustituido se puede dividir mediante el tratamiento con un ácido adecuado, por ejemplo, ácido fórmico o ácido trifluoroacético; el benziloxicarbonilamino no sustituido o sustituido se puede dividir, por ejemplo, por medio de una hidrogenólisis, es decir, mediante el tratamiento con hidrógeno en la presencia de un catalizador de hidrogenación adecuado, tal como un catalizador de paladio; triarilmetilamino o formilamino no sustituido o sustituido se pueden dividir, por ejemplo, mediante tratamiento con un ácido, tal como un ácido mineral, por ejemplo ácido clorhídrico, o con un ácido orgánico, por ejemplo ácido fórmico, acético o trifluoroacético, donde sea apropiado en la presencia de agua; y un grupo amino protegido por un grupo sililo orgánico se puede liberar, por ejemplo, por medio de hidrólisis o alcohólisis. Un grupo amino protegido por 2-haloacetilo, por ejemplo 2-cloroacetilo, se pueden liberar mediante tratamiento con tiourea en la presencia de una base, o con una sal de tiolato, tal como un tiolato de metal alcalino, de tiourea, y la solvólisis posterior, tal como alcohólisis o hidrólisis, del producto de condensación resultante. Un grupo amino protegido por sililetoxicarbonilo 2-sustituido se puede convertir en el grupo amino libre también por tratamiento con una sal de ácido fluorhídrico que produce aniones fluoruro.A protected amino group is released in a manner known per se and, according to the nature of the protected groups, in several ways, preferably by solvolysis or reduction. 2-Halo-lower alkoxycarbonylamino (where it is appropriate after the conversion of a lower 2-bromo-alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be divided, for example, by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. The aroylmethoxycarbonylamino can also be divided by treatment with a nucleophilic reagent, preferably salt-forming, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example, sodium dithionite. The unsubstituted or substituted diphenylmethoxycarbonylamino, lower tert-alkoxycarbonylamino or trisubstituted 2-silyloxycarbonylamino can be divided by treatment with a suitable acid, for example, formic acid or trifluoroacetic acid; unsubstituted or substituted benzyloxycarbonylamino can be divided, for example, by hydrogenolysis, that is, by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst; unsubstituted or substituted triarylmethylamino or formylamino can be divided, for example, by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or with an organic acid, for example formic, acetic or trifluoroacetic acid, where appropriate in the presence of water; and an amino group protected by an organic silyl group can be released, for example, by hydrolysis or alcohololysis. An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can be released by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, thiourea, and sololysis subsequent, such as alcohololysis or hydrolysis, of the resulting condensation product. An amino group protected by 2-substituted silylethoxycarbonyl can also be converted into the free amino group by treatment with a salt of hydrofluoric acid that produces fluoride anions.
Proceso b)Process b)
1-Aril-alquilo inferior Z' en un compuesto de la fórmula VI es especialmente 1-feniletilo y también bencilo.1-Aryl-alkyl lower Z 'in a compound of formula VI is especially 1-phenylethyl and also benzyl.
El compuesto de la fórmula VI está en equilibrio tautomérico (forma lactama/lactim), la forma lactama (fórmula VI) presumiblemente de manera predominante. La fórmula VI se utiliza para representar las dos posibles formas de equilibrio.The compound of formula VI is in equilibrium tautomeric (lactam / lactim form), lactam form (formula VI) presumably predominantly. Formula VI is used to represent the two possible forms of balance.
La forma lactim tiene la fórmula VIaThe lactim form has the formula VIa
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
en la cual los radicales son como se definieron para los compuestos de fórmula VI.in which the radicals are like were defined for the compounds of formula SAW.
La presente invención también se relaciona con los compuestos novedosos de la fórmula VI y VIa.The present invention also relates to the novel compounds of the formula VI and VIa.
El agente deshidratante emplea especialmente un agente deshidratante químico fuerte, en particular pentóxido de fósforo (P_{4}O_{10}).The dehydrating agent especially employs a strong chemical dehydrating agent, in particular pentoxide of phosphorus (P4 O10).
Una amina terciaria adecuada es principalmente amonio sustituido por tres radicales libres seleccionados independientemente uno del otro de alquilo, especialmente alquilo inferior, tal como metilo o etilo, y cicloalquilo que tiene 3 a 7 átomos de carbono, especialmente ciclohexilo, por ejemplo N,N-dimetil-N-ciclohexilamina, N-etil-N,N-diisopropilamina o trietilamina, o, adicionalmente, también piridina, N-metilmorfolino o 4-dimetilaminopiridina.A suitable tertiary amine is primarily ammonium substituted by three selected free radicals independently of each other alkyl, especially alkyl lower, such as methyl or ethyl, and cycloalkyl having 3 to 7 carbon atoms, especially cyclohexyl, for example N, N-dimethyl-N-cyclohexylamine, N-ethyl-N, N-diisopropylamine or triethylamine, or, additionally, also pyridine, N-methylmorpholino or 4-dimethylaminopyridine.
La reacción entre la pirroloprimidinona de la fórmula VI y el derivado de anilina de la fórmula V tienen lugar a temperatura elevada, por ejemplo, a 200 a 250ºC.The reaction between the pyrroloprimidinone of the formula VI and the aniline derivative of formula V take place at high temperature, for example, at 200 to 250 ° C.
\newpage\ newpage
Proceso e)Process and)
La reacción se lleva a cabo preferiblemente en un disolvente inerte adecuado, por ejemplo un alcohol adecuado, tal como especialmente metanol, a temperaturas desde aproximadamente +10ºC a +100ºC, preferiblemente a temperaturas de ebullición de la mezcla de reacción. En este caso el derivado de hidroxilamina de la fórmula VIII se emplea preferiblemente como una sal y se convergerte en la base libre mediante la adición de una solución acuosa de acetato de sodio a la mezcla de reacción.The reaction is preferably carried out in a suitable inert solvent, for example a suitable alcohol, such as especially methanol, at temperatures from about + 10 ° C to + 100 ° C, preferably at boiling temperatures of the reaction mixture. In this case the hydroxylamine derivative of the Formula VIII is preferably used as a salt and is converge on the free base by adding a solution aqueous sodium acetate to the reaction mixture.
Proceso f)Process F)
Un derivado de ácido carboxílico reactivo de un compuesto de la fórmula I en la cual uno de los radicales R_{1} y R_{2} es carboxilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I es, por ejemplo, un éster adecuado, tal como especialmente un etil éster.A reactive carboxylic acid derivative of a compound of the formula I in which one of the radicals R1 and R2 is carboxyl and the other substituents are as defined above for the compounds of formula I is, for example, a suitable ester, such as especially an ethyl ester.
Donde es posible, por ejemplo si el morfolino es la amina de la fórmula VII, la amina de la fórmula VII se puede utilizar en si misma como un disolvente. En otros casos un disolvente inerte adecuado, por ejemplo, dimetilformamida, junto con TPTU (O-(1,2-dihidro-2-oxo-1-piridil)-N,N,N',N'-tetrametiluronio terafluoroborato se utiliza. La reacción se lleva a cabo preferiblemente a temperaturas desde aproximadamente +10ºC a +150ºC, preferiblemente desde temperatura ambiente a 100ºC.Where is it possible, for example if the morpholino is the amine of the formula VII, the amine of the formula VII can be use itself as a solvent. In other cases a suitable inert solvent, for example, dimethylformamide, together with TPTU (O- (1,2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium Terafluoroborate is used. The reaction is carried out. preferably at temperatures from about + 10 ° C to + 150 ° C, preferably from room temperature to 100 ° C.
Proceso g)Process g)
El reactivo de Lawsson es 2,4-di[4-metoxifenil]-1,3-ditia-2,4-difosfetano-2,4-disulfuro y está comercialmente disponible, entre otros de SIGMA, FLUKA etc.. La reacción se lleva a cabo preferiblemente en un disolvente inerte adecuado, por ejemplo, un éter adecuado, tal como especialmente éter cíclico, por ejemplo, tetrahidrofurano, a temperaturas desde aproximadamente 50ºC a 150ºC, preferiblemente a temperatura de ebullición de la mezcla de reacción.Lawsson's reagent is 2,4-di [4-methoxyphenyl] -1,3-dithia-2,4-diphosphethane-2,4-disulfide and is commercially available, among others from SIGMA, FLUKA etc. The reaction is preferably carried out in an inert solvent. suitable, for example, a suitable ether, such as especially ether cyclic, for example, tetrahydrofuran, at temperatures from about 50 ° C to 150 ° C, preferably at a temperature of boiling the reaction mixture.
Proceso h)Process h)
R_{13} es preferiblemente alquilo inferior, tal como especialmente etilo, o fenilo sustituido por halo, alquilo inferior, hidroximetilo, aminometilo, hidroxilo, alcanoiloxi inferior, alcoxi inferior, carboxilo, alcanoilo inferior, benzoilo, alcoxicarbonilo inferior, carbamoilo, N-alquilcarbamoilo inferior, N,N-di-alquilcarbamoilo inferior, ciano, amino, alcanoilamino inferior, alquilamino inferior, N,N-di-alquilamino inferior o trifluorometilo o no sustituido, en particular 4-metoxifenilo.R 13 is preferably lower alkyl, such as especially ethyl, or phenyl substituted by halo, alkyl lower, hydroxymethyl, aminomethyl, hydroxy, alkanoyloxy lower, lower alkoxy, carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino, N, N-di-lower alkylamino or trifluoromethyl or unsubstituted, in particular 4-methoxyphenyl.
La reacción se lleva a cabo preferiblemente en un disolvente inerte adecuado, por ejemplo, un alcohol adecuado, tal como especialmente metanol, o un éter adecuado, por ejemplo dioxano, a temperaturas desde aproximadamente +20ºC a +180ºC, preferiblemente a la temperatura de ebullición de la mezcla de reacción.The reaction is preferably carried out in a suitable inert solvent, for example, a suitable alcohol, such as especially methanol, or a suitable ether, for example dioxane, at temperatures from about + 20 ° C to + 180 ° C, preferably at the boiling temperature of the mixture of reaction.
Proceso i)Process i)
La reacción se lleva a cabo preferiblemente en un disolvente inerte adecuado, por ejemplo, un alcohol adecuado, tal como especialmente 1-metoxietanol, en la presencia de cloruro de litio, por ejemplo una y media veces la cantidad molar de cloruro de litio, a temperaturas desde aproximadamente +20ºC a +180ºC, preferiblemente a la temperatura de ebullición de la mezcla de reacción.The reaction is preferably carried out in a suitable inert solvent, for example, a suitable alcohol, such as especially 1-methoxyethanol, in the presence of lithium chloride, for example one and a half times the molar amount of lithium chloride, at temperatures from approximately + 20 ° C to + 180 ° C, preferably at the temperature of boiling the reaction mixture.
Proceso j)Process j)
La reacción se lleva a cabo preferiblemente en un disolvente inerte adecuado, por ejemplo, dimetilformamida, en la presencia de carbonato de hidrógeno de sodio, a temperaturas desde aproximadamente 0ºC a +180ºC, preferiblemente a la temperatura ambiente. En este caso el yoduro de alquilo inferior, tal como especialmente yoduro de metilo, se agrega preferiblemente como una solución, por ejemplo, solución 1 M, en un éter adecuado, tal como dioxano.The reaction is preferably carried out in a suitable inert solvent, for example, dimethylformamide, in the presence of sodium hydrogen carbonate, at temperatures from about 0 ° C to + 180 ° C, preferably at the temperature ambient. In this case the lower alkyl iodide, such as especially methyl iodide, it is preferably added as a solution, for example, 1 M solution, in a suitable ether, such as dioxane
Proceso k)Process k)
X es preferiblemente cloro.X is preferably chlorine.
La reacción se lleva a cabo preferiblemente en un disolvente inerte y anhidro adecuado, por ejemplo, dimetilacetamida, a temperaturas desde aproximadamente -30ºC a +70ºC, preferiblemente a 0ºC.The reaction is preferably carried out in a suitable inert and anhydrous solvent, for example, dimethylacetamide, at temperatures from about -30 ° C to + 70 ° C, preferably at 0 ° C.
Proceso l)Process l)
R_{17} es preferiblemente metilo.R 17 is preferably methyl.
La reacción se lleva a cabo preferiblemente en un disolvente inerte y anhidro adecuado, por ejemplo, un éter, tal como tetrahidrofurano, en la presencia de trietilamina a temperaturas desde aproximadamente -10ºC a +70ºC, preferiblemente a temperatura ambiente.The reaction is preferably carried out in a suitable inert and anhydrous solvent, for example, an ether, such as tetrahydrofuran, in the presence of triethylamine a temperatures from about -10 ° C to + 70 ° C, preferably at room temperature.
Proceso m)Process m)
La reacción se lleva a cabo preferiblemente en un disolvente inerte y anhidro adecuado, por ejemplo, un éter, tal como tetrahidrofurano, ventajosamente en la presencia de dimetilacetamida a temperaturas desde aproximadamente 0ºC a +150ºC, preferiblemente a la temperatura de ebullición de la mezcla de reacción.The reaction is preferably carried out in a suitable inert and anhydrous solvent, for example, an ether, such as tetrahydrofuran, advantageously in the presence of dimethylacetamide at temperatures from about 0 ° C to + 150 ° C, preferably at the boiling temperature of the mixture of reaction.
Proceso n)Process n)
La reacción se lleva a cabo preferiblemente en un disolvente inerte y anhidro adecuado, por ejemplo, un éter, tal como tetrahidrofurano, ventajosamente en la presencia de dimetilacetamida a temperaturas desde aproximadamente 0ºC a +150ºC, preferiblemente a la temperatura de ebullición de la mezcla de reacción.The reaction is preferably carried out in a suitable inert and anhydrous solvent, for example, an ether, such as tetrahydrofuran, advantageously in the presence of dimethylacetamide at temperatures from about 0 ° C to + 150 ° C, preferably at the boiling temperature of the mixture of reaction.
Proceso o)Process or)
La reacción se lleva a cabo preferiblemente en un disolvente inerte y anhidro adecuado, por ejemplo, un éter, tal como dioxano, ventajosamente en la presencia de 2,6-lutidina, a temperaturas desde aproximadamente -30ºC a +150ºC, preferiblemente a temperatura ambiente.The reaction is preferably carried out in a suitable inert and anhydrous solvent, for example, an ether, such as dioxane, advantageously in the presence of 2,6-lutidine, at temperatures from about -30 ° C to + 150 ° C, preferably at room temperature.
Los materiales de partida de la fórmula IV son novedosos y la presente invención también se relaciona con éstos. Ellos se pueden preparar mediante procesos análogos a aquellos descritos en German Offenlegungsschrift No. 28 18 676 (publicado el 8 de noviembre de 1979) y German Offenlegungsschrift No. 30 36 390, (publicado el 13 de mayo de 1982).The starting materials of formula IV are novel and the present invention also relates to these. They can be prepared by processes analogous to those described in German Offenlegungsschrift No. 28 18 676 (published on November 8, 1979) and German Offenlegungsschrift No. 30 36 390, (published May 13, 1982).
El material de partida de la fórmula IV en el cual X es cloro se obtiene, por ejemplo, de una compuesto análogo a la fórmula IV en el cual X es hidroxilo (ver los compuestos de fórmula VIa) mediante la reacción con oxicloruro de fósforo (cloruro de fosforilo, P(=O)Cl_{3}) con la exclusión de humedad a temperatura de reflujo. Si se desea, la reacción adicional del material de partida de la fórmula IV así obtenida en la cual X es cloro se puede llevar acabo con un derivado de anilina de la fórmula V en el mismo recipiente, es decir, como una reacción "one-pot". Para este propósito, después de que la reacción con oxicloruro de fósforo se completa, la mezcla de reacción se evapora hasta sequedad, suspendida utilizando un disolvente adecuado, tal como n-butanol, y reaccionando ademas con el derivado de anilina de la fórmula V.The starting material of formula IV in the which X is chlorine is obtained, for example, from a compound analogous to formula IV in which X is hydroxyl (see compounds of formula VIa) by reaction with phosphorus oxychloride (phosphoryl chloride, P (= O) Cl 3) with the exclusion of humidity at reflux temperature. If desired, the reaction additional starting material of formula IV thus obtained in which X is chlorine can be carried out with an aniline derivative of the formula V in the same container, that is, as a reaction "one-pot" For this purpose, after the reaction with phosphorus oxychloride is complete, the mixture of reaction is evaporated to dryness, suspended using a suitable solvent, such as n-butanol, and further reacting with the aniline derivative of the formula V.
Un compuesto análogo de fórmula IV en el cual X es hidroxilo se obtiene, por ejemplo, de un compuesto de fórmula XV.An analogous compound of formula IV in which X hydroxyl is obtained, for example, from a compound of formula XV.
En la cual los símbolos son como se definió anteriormente, mediante la reacción con ácido fórmico, que es preferiblemente empleado en exceso con relación al compuesto de fórmula XV, por ejemplo, con un exceso de 10 a 30 molar donde es apropiado en la presencia de disolventes inertes tal como dimetil formamida, a temperatura elevada, por ejemplo a temperaturas de 80ºC hasta temperatura de ebullición.In which the symbols are as defined above, by reaction with formic acid, which is preferably used in excess in relation to the compound of formula XV, for example, with an excess of 10 to 30 molar where it is appropriate in the presence of inert solvents such as dimethyl formamide, at elevated temperature, for example at temperatures of 80 ° C to boiling temperature.
Alternativamente, un compuesto análogo a la fórmula IV en la cual X es hidroxilo y los otros símbolos son como se definió anteriormente se obtiene, por ejemplo, de un compuesto de fórmula XVI.Alternatively, a compound analogous to the formula IV in which X is hydroxyl and the other symbols are like defined above is obtained, for example, from a compound of formula XVI.
En la cual R_{19} es alquilo inferior, tal como especialmente etilo, y los otros símbolos son como se definió anteriormente, mediante la reacción con grandes excesos de formamida en una mezcla de dimetilformamida anhidra y ácido fórmico. La reacción se lleva a cabo a temperatura elevada, por ejemplo desde 100ºC a 150ºC, y preferiblemente bajo gas protector.In which R 19 is lower alkyl, such as especially ethyl, and the other symbols are as defined previously, by reaction with large excesses of formamide in a mixture of anhydrous dimethylformamide and formic acid. The reaction is carried out at elevated temperature, for example from 100 ° C to 150 ° C, and preferably under protective gas.
La presente invención también se relaciona con materiales de partida novedosos de las fórmulas XV y XVI.The present invention also relates to Novel starting materials of formulas XV and XVI.
El 1-(Z')-2-amino-3-cianopirroles de la fórmula XV utilizados como intermedios se pueden preparar con buenos rendimientos mediante métodos que son conocidos per se y han sido publicados [ver, por ejemplo, Roth, H.J., y Eger, K., Arch. Pharmaz. 308, 179 (1975)]. Para este propósito, por ejemplo, un compuesto de la fórmula XVII.The 1- (Z ') - 2-amino-3-cyanopyrroles of formula XV used as intermediates can be prepared in good yields by methods that are known per se and have been published [see, for example, Roth, HJ, and Eger, K., Arch. Pharmaz. 308, 179 (1975)]. For this purpose, for example, a compound of the formula XVII.
Reacciona primero con una amina de la fórmula Z'-NH_{2} para dar una compuesto de fórmula XVIII.React first with an amine of the formula Z'-NH2 to give a compound of formula XVIII.
Que es luego convertido a malononitrilo de
fórmula CH_{2}(CN)_{2} en el intermedio deseado de
la fórmula XV. En detalle, la reacción con la amina
Z'-NH_{2} se lleva a cabo bajo condiciones de
condensación habituales, por ejemplo en la presencia de cantidades
catalíticas de un ácido fuerte, por ejemplo ácido clorhídrico o
ácido p-toluenosulfonico, a temperatura elevada
(preferiblemente a calor de ebullición) en un disolvente adecuado,
por ejemplo, benzeno o tolueno, con la separación de agua, para dar
la respectiva \alpha-amino cetona de la fórmula
XVIII. La última no se aísla pero es inmediatamente condensada con
malononitrilo con calentamiento y con separación adicional de agua
si es necesario con la adición de la pequeña cantidad de base, tal
como piperidina, o un compuesto de fórmula
XV.Which is then converted to malononitrile of formula CH2 (CN) 2 in the desired intermediate of formula XV. In detail, the reaction with the Z'-NH2 amine is carried out under usual condensation conditions, for example in the presence of catalytic amounts of a strong acid, for example hydrochloric acid or p-toluenesulfonic acid, at temperature elevated (preferably at boiling heat) in a suitable solvent, for example, benzene or toluene, with the separation of water, to give the respective α-amino ketone of the formula XVIII. The latter is not isolated but is immediately condensed with malononitrile with heating and with additional water separation if necessary with the addition of the small amount of base, such as piperidine, or a compound of formula
XV.
Los compuesto de fórmula XVI utilizados como intermedios se obtiene, por ejemplo, al hacer reaccionar un éster de alquilo inferior de ácido 2-amidinoacetico de fórmula XIXThe compounds of formula XVI used as intermediates are obtained, for example, by reacting an ester lower alkyl of 2-amidinoacetic acid of formula XIX
En donde R_{19} es como se definió anteriormente con un derivado de 2-X-1-R_{2}-etan-1-una de la fórmula XX.Where R_ {19} is as defined previously with a derivative of 2-X-1-R2 -etan-1-una of the formula XX.
En la cual los símbolos son como se definió anteriormente. El grupo saliente X es preferiblemente bromo. El éster de alquilo inferior de ácido 2-aminoacetico de fórmula XIX se libera de sustancia adición de ácido, tal como especialmente su clorhidrato, antes de iniciar la reacción con la ayuda de cantidades equinormales de una base, tal como especialmente etoxido de sodio, con enfriamiento de hielo. La reacción se lleva acabo en un disolvente adecuado, tal como especialmente un alcanol inferior, tal como preferiblemente etanol, a temperaturas preferidas de desde 0ºC a 50ºC especialmente a temperatura ambiente.In which the symbols are as defined previously. The leaving group X is preferably bromine. He lower alkyl ester of 2-aminoacetic acid of Formula XIX is released from acid addition substance, such as especially its hydrochloride, before starting the reaction with the support of equinormal amounts of a base, such as especially sodium ethoxide, with ice cooling. The reaction is carried out in a suitable solvent, such as especially a lower alkanol, such as preferably ethanol, at preferred temperatures from 0 ° C to 50 ° C especially at room temperature.
Un compuesto de partida de la fórmula I en la cual uno de los radicales R_{1} y R_{2} es formilo, carboxilo, alcoxi carbonilo inferior, ciano, carbamoilo, tiocarbamoilo, aminofenilo o tetrazol-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario son protegidos por grupos protectores fácilmente removibles, son obtenidos como se explico a manera de ejemplo en la sección de ejemplos. Una persona experta en la técnica puede transferir las reacciones ejemplificadas especificas sin mayor esfuerzo a los compuestos que tienen otros radicales R y R_{1} o R_{2} que aquellos que son específicamente ejemplificados, siempre y cuando los grupos funcionales libres presentes en el radical R estén protegidos por grupos protectores fácilmente removibles, si es necesario, si estos interfieren con la reacción deseada. En muchos casos, especialmente si, por ejemplo, R es halógeno, no es necesaria protección.A starting compound of the formula I in the which one of the radicals R 1 and R 2 is formyl, carboxyl, lower alkoxycarbonyl, cyano, carbamoyl, thiocarbamoyl, aminophenyl or tetrazol-5-yl and the Other substituents are as defined above for compounds of formula I, the free functional groups present in the radical R if necessary are protected by protective groups easily removable, are obtained as explained by way of example in the examples section. A person skilled in the art you can transfer the specific exemplified reactions without greater effort to compounds that have other radicals R and R_ {1} or R2_ than those that are specifically exemplified, as long as the free functional groups present in the radical R are protected by protecting groups easily removable, if necessary, if they interfere with the desired reaction In many cases, especially if, for example, R It is halogen, no protection is necessary.
Los compuestos libres de fórmula I que tienen propiedades formadoras de sal que son obtenibles de acuerdo con el proceso se puede convertir en sus sales de manera conocida per se, por ejemplo al tratar con ácidos o derivados adecuados de estos, por ejemplo mediante la adición del ácido apropiado del compuesto en la fórmula I disuelto en un disolvente adecuado, por ejemplo un éter, tal como un éter cíclico, especialmente dioxano o en tetrahidrofurano particular.The free compounds of formula I having salt-forming properties that are obtainable according to the process can be converted into their salts in a manner known per se , for example by treating with suitable acids or derivatives thereof, for example by adding the Appropriate acid of the compound in formula I dissolved in a suitable solvent, for example an ether, such as a cyclic ether, especially dioxane or in particular tetrahydrofuran.
Las mezclas de los isómeros obtenibles de acuerdo con la invención se pueden separar en isómeros individuales de manera conocido per se; los racematos se pueden separar, por ejemplo, al formar sales con reactivos formadores de sales óptimamente puros y separar la mezcla de diastereomeros así obtenibles, por ejemplo por medio de cristalización fraccional.Mixtures of the isomers obtainable according to the invention can be separated into individual isomers in a manner known per se ; racemates can be separated, for example, by forming salts with optimally pure salt-forming reagents and separating the mixture of diastereomers thus obtainable, for example by means of fractional crystallization.
Las reacciones descritas anteriormente se pueden llevar a cabo bajo condiciones de reacción conocidas per se en la ausencia o, de costumbre, la presencia de disolventes o diluyentes, preferiblemente aquellos que son inertes hacia los reactivos utilizados y son disolventes para estos, en la ausencia o presencia de catalizadores, agentes de condensación (por ejemplo pentóxido de fósforo) o agentes neutralizantes, por ejemplo bases, especialmente bases de nitrógeno, tal como hiclorhidrato de trietilamina, dependiendo de la naturaleza de la reacción y/o los reactivos a temperatura reducida, normal o elevada, por ejemplo en un rango de temperatura de aproximadamente -80ºC a aproximadamente 200ºC, preferiblemente desde aproximadamente -250ºC a aproximadamente 150ºC, por ejemplo en el punto de ebullición del disolvente utilizado, bajo presión atmosférica o en un recipiente cerrado, cuando sea apropiado bajo presión y/o en una atmósfera inerte, por ejemplo bajo atmósfera de nitrógeno.The reactions described above can be carried out under reaction conditions known per se in the absence or, usually , the presence of solvents or diluents, preferably those that are inert towards the reagents used and are solvents for these, in the absence or presence of catalysts, condensing agents (for example phosphorus pentoxide) or neutralizing agents, for example bases, especially nitrogen bases, such as triethylamine hydrochloride, depending on the nature of the reaction and / or the reagents at reduced temperature, normal or elevated, for example in a temperature range of about -80 ° C to about 200 ° C, preferably from about -250 ° C to about 150 ° C, for example at the boiling point of the solvent used, under atmospheric pressure or in a closed container, when appropriate under pressure and / or in an inert atmosphere, for example under a nit atmosphere rheogenic
Las condiciones de reacción específicas dadas en cada caso se prefieren.The specific reaction conditions given in Each case is preferred.
Los disolventes o diluyentes son, por ejemplo, agua, alcoholes, por ejemplo, hidróxidos de alquilo inferior, tales como metanol, etanol, propanol o especialmente butanol, dioles, tales como etilen glicol, trioles, tales como glicerol, o aril alcoholes tales como fenol, amidas ácidas, por ejemplos amidas de ácido carboxílico, tales como dimetil formamida, dimetilacetamida o 1,3-dimetil-3,4,5,6-tetrahidro-2(1H)-pirimidinona (DMPU) ácidos carboxílicos, especialmente ácido fórmico o ácido acético amidas de ácidos orgánicos, tales como triamida de ácido hexametilfosforico, éteres, por ejemplo, éteres cíclicos, tales como tetrahidrofurano o dioxano o éteres acíclicos, tales como dietiléter o etilen glicol dimetil éter, hidrocarburos halogenados, tales como halo-alcanos inferiores, por ejemplo cloruro de metileno o cloroformo, cetonas, tales como acetonas, nitrilo, tales como acetonitrilo, anhídridos ácidos, tales como anhídrido acético, ésteres, tales como acetato de etilo, bis-alcanosulfinas, tales como dimetilsulfoxido, compuestos heterocíclicos que contiene nitrógeno, tales como piridina, hidrocarburos, por ejemplo alcanos inferiores, tales como heptano, o compuestos aromáticos, tales como benzeno, tolueno o xileno(s) o mezclas de estos disolventes es posible seleccionar los disolventes adecuados en cada caso para las reacciones anteriormente mencionadas.Solvents or diluents are, for example, water, alcohols, for example, lower alkyl hydroxides, such like methanol, ethanol, propanol or especially butanol, diols, such as ethylene glycol, triols, such as glycerol, or aryl alcohols such as phenol, acid amides, for example amides of carboxylic acid, such as dimethyl formamide, dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU) carboxylic acids, especially formic acid or acid acetic organic acid amides, such as acid triamide hexamethylphosphoric, ethers, for example, cyclic ethers, such as tetrahydrofuran or dioxane or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as lower halo-alkanes, for example methylene chloride or chloroform, ketones, such as ketones, nitrile, such as acetonitrile, acid anhydrides, such as acetic anhydride, esters, such as ethyl acetate, bis-alkanesulphines, such as dimethyl sulfoxide, nitrogen-containing heterocyclic compounds, such as pyridine, hydrocarbons, for example lower alkanes, such as heptane, or aromatic compounds, such as benzene, toluene or xylene (s) or mixtures of these solvents is possible select the appropriate solvents in each case for the reactions mentioned above.
Los procesos de costumbres son utilizados para trabajar los compuestos obtenibles de la fórmula I o sus sales, por ejemplo solvolisis o reactivos en exceso; recristalización; cromatografía, por ejemplo partición, cromatografía de ión o gel; partición entre las fases de los disolventes inorgánicos y orgánicos; extracción simple o múltiple, especialmente después de acidificar o incrementar la basicidad del contenido de sal, secar sobre sales giroscópica; digerir; filtrar; lavar; disolver; evaporar (si es necesario in vacuo o bajo alto vacío); destilación; cristalización, por ejemplo de los compuestos obtenidos en forma de aceite o del licor madre, sembrado con un cristal del producto final también es posible; o una combinación de dos o mas de las etapas de trabajo mencionadas, que también se pueden emplear repetidamente, etc.Customs processes are used to work the compounds obtainable from the formula I or their salts, by example solvolysis or excess reagents; recrystallization; chromatography, for example partition, ion or gel chromatography; partition between the phases of inorganic solvents and organic; single or multiple extraction, especially after acidify or increase the basicity of salt content, dry about gyroscopic salts; to digest; filter; to wash; dissolve; evaporate (if necessary in vacuo or under high vacuum); distillation; crystallization, for example of the compounds obtained in the form of oil or mother liquor, seeded with a product glass final is also possible; or a combination of two or more of the mentioned work stages, which can also be used repeatedly, etc.
Los materiales de partida y los intermedios se pueden utilizar en forma pura, por ejemplo después de trabajar, justo como se menciono, en forma parcialmente purificada o alternativamente, por ejemplo, directamente como un producto crudo.Starting materials and intermediates are they can use in pure form, for example after working, just as mentioned, partially purified or alternatively, for example, directly as a product raw.
Los compuestos que incluyen sus sales, también se pueden obtener en la forma de hidratos, o sus cristales pueden incluir por ejemplo, el disolvente utilizado para cristalización. La presente invención también relaciona a estos hidratos o solvatos de los compuestos de fórmula I y los materiales de partida descritos que pertenecen a la materia objeto de la invención.Compounds that include their salts, too they can be obtained in the form of hydrates, or their crystals can include, for example, the solvent used for crystallization. The The present invention also relates to these hydrates or solvates of the compounds of formula I and the starting materials described which belong to the subject matter of the invention.
En vista de la cercana relación entre los compuestos de fórmula I en forma libre y en la forma de sus sales, anteriormente y ha continuación los compuestos libres y sus sales va hacer entendidos como significando también las sales correspondientes y los compuestos libres, respectivamente, según se ha apropiado y conveniente, siempre y cuando los compuestos contengan grupos formadores de sal. Lo mismo aplica a los hidratos y ha los solvatos.In view of the close relationship between compounds of formula I in free form and in the form of their salts, previously and then the free compounds and their salts goes make understood as also meaning salts corresponding and free compounds, respectively, as has appropriate and convenient, as long as the compounds contain salt forming groups. The same applies to hydrates and He has the solvates.
En el proceso de la presente invención, los materiales de partida empleados son preferiblemente aquellos que conducen a los compuestos novedosos de la fórmula I descrita al inicio y que es especialmente valiosa.In the process of the present invention, the starting materials used are preferably those that lead to the novel compounds of the formula I described at Start and that is especially valuable.
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La invención también se relaciona con aquellas formas del proceso en la cual un compuesto obtenible como un intermedio en una tapa del proceso se utiliza como un material de partida y las etapas restantes del proceso son llevadas a cabo o en las cuales se forma un material de partida bajo las condiciones de reacción o se utiliza en la forma de un derivado por ejemplo una sal de este.The invention also relates to those forms of the process in which a compound obtainable as a intermediate in a process lid is used as a material of heading and the remaining stages of the process are carried out or in which forms a starting material under the conditions of reaction or is used in the form of a derivative for example a Get out of this.
Composiciones farmacéuticas, su preparación y el uso de acuerdo con la invención de los compuestos de fórmula I y de las composiciones que comprenden estos compuestos como ingrediente activo.Pharmaceutical compositions, their preparation and the use according to the invention of the compounds of formula I and of the compositions comprising these compounds as an ingredient active.
La presente invención también se relaciona con composiciones farmacéuticas que comprende uno de los compuestos de la fórmula I como ingrediente activo que se puede utilizar especialmente para el tratamiento de las enfermedades mencionadas al inicio. Las composiciones para administración enteral, tales como nasal, bucal, rectal, o, especialmente, administración oral, y para administración parenteral, tal como administración intravenosa, intramuscular o subcutánea animales de sangre caliente, especialmente humanos, se prefiere especialmente. Las composiciones que comprenden el ingrediente activo por si mismo o, preferiblemente, junto con un portador farmacéuticamente aceptable. La dosis del ingrediente activo dependen de la enfermedad hacer tratada y de las especies, su edad, el peso y la condición individual, los datos farmacocinéticas individuales, la enfermedad hacer tratada y también luego del modo de administración.The present invention also relates to pharmaceutical compositions comprising one of the compounds of Formula I as an active ingredient that can be used especially for the treatment of the mentioned diseases at the beginning. Compositions for enteral administration, such as nasal, buccal, rectal, or, especially, oral administration, and for parenteral administration, such as intravenous administration, intramuscular or subcutaneous warm-blooded animals, especially human, it is especially preferred. The compositions which comprise the active ingredient itself or, preferably, together with a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the disease do treated and species, their age, weight and condition individual, individual pharmacokinetic data, disease make treated and also after administration mode.
La invención también se relaciona con composiciones farmacéuticas para uso en un método para el tratamiento terapéutico del cuerpo humano o animal, con un proceso para la preparación de este (especialmente como composiciones para el tratamiento de tumores) y con un método para tratar enfermedades neoplásticas, especialmente aquellos mencionados anteriormente.The invention also relates to pharmaceutical compositions for use in a method for therapeutic treatment of the human or animal body, with a process for the preparation of this (especially as compositions for the treatment of tumors) and with a method to treat diseases Neoplastic, especially those mentioned above.
Se prefiere una composición farmacéutica que es adecuada para la administración animales de sangre caliente, especialmente un humano, que sufre de una enfermedad que responde a la inhibición de una proteína quinasa, por ejemplo soriasis o un tumor que comprende un compuesto de fórmula I o una sal de éste si los grupos formadores de sal están presentes, en una cantidad efectiva para la inhibición de la proteína quinasa, junto con por lo menos un portador farmacéuticamente aceptable.A pharmaceutical composition that is preferred is preferred. suitable for administration of warm-blooded animals, especially a human, who suffers from a disease that responds to inhibition of a protein kinase, for example psoriasis or a tumor comprising a compound of formula I or a salt thereof if salt forming groups are present, in an amount effective for protein kinase inhibition, along with by at least one pharmaceutically acceptable carrier.
Las composiciones farmacéuticas comprende desde aproximadamente 1% a aproximadamente 95% del ingrediente activo, las formas de administración en forma de dosis única preferiblemente comprende desde aproximadamente 20% a aproximadamente 90% del ingrediente activo y las formas de administración que no son en forma de dosis única preferiblemente comprenden desde aproximadamente 5% a aproximadamente 20% del ingrediente activo. Las formas de dosis unitaria son, por ejemplo, tabletas recubiertas con azúcar, tabletas, ampollas, frascos, supositorios o cápsulas. Otras formas de administración son, por ejemplo, ungüentos, cremas, pastas, espumas, tinturas, labiales, gotas, pulverizados, dispersiones, etc. Ejemplos son cápsulas, que comprende desde aproximadamente 0.5 g a aproximadamente 1.0 g del ingrediente activo.The pharmaceutical compositions comprise from about 1% to about 95% of the active ingredient, single dose administration forms preferably it comprises from about 20% to about 90% of active ingredient and forms of administration that are not in single dose form preferably comprise from about 5% to about 20% of the active ingredient. The unit dose forms are, for example, tablets coated with sugar, tablets, ampoules, jars, suppositories or capsules. Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, powdered, dispersions, etc. Examples are capsules, which comprises from about 0.5 g to about 1.0 g of the ingredient active.
Las composiciones farmacéuticas de la presente invención se preparan de manera conocida per se, por ejemplo por medio de mezcla convencional, granulación, recubrimiento con azúcar, procesos de disolución o liofilización.The pharmaceutical compositions of the present invention are prepared in a manner known per se , for example by means of conventional mixing, granulation, sugar coating, dissolution or lyophilization processes.
Las soluciones del ingrediente activo son utilizadas preferiblemente, y también las suspensiones o dispersiones para hacer soluciones acuosas especialmente isotónicas precisas las cuales, por ejemplo, en el caso de las composiciones liofilizadas que comprende el ingrediente activo por si mismas o junto con un portador, por ejemplo manitol se pueden preparar antes de uso. Las composiciones farmacéuticas se pueden esterilizar y/o pueden comprender excipientes, por ejemplo preservantes, estabilizadores, agentes humectantes y/o emulsificadores, solubilizantes, sales para regular la presión asmótica y/o amortiguadores, y se preparan de manera conocida per se, por ejemplo por medio de procesos de disolución y liofilización convencionales. Las soluciones o suspensiones mencionadas pueden comprende sustancias que incrementan la viscosidad, tales como carboximetil celulosa de sodio, carboximetil celulosa, dextrano, polivinilpirrolidona o gelatina.The active ingredient solutions are preferably used, and also the suspensions or dispersions to make especially precise aqueous isotonic solutions which, for example, in the case of lyophilized compositions comprising the active ingredient itself or together with a carrier, by Example mannitol can be prepared before use. The pharmaceutical compositions may be sterilized and / or may comprise excipients, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating asmotic pressure and / or buffers, and are prepared in a manner known per se , for example. by means of conventional dissolution and lyophilization processes. The mentioned solutions or suspensions may comprise substances that increase viscosity, such as sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone or gelatin.
La suspensiones en aceite comprenden como el componente en aceite los aceites vegetales, sintéticos o semi-sintéticos de costumbre para propósitos de inyección. Se puede mencionar como tales ésteres de ácido graso especialmente líquidos que contiene como el componente ácido un ácido graso de cadena larga que tiene 8-22, especialmente 12-22, átomos de carbono, por ejemplo ácido laurico, ácido tridecilico, ácido mirístico, ácido pentadecilico, ácido palmítico, ácido margárico, ácido esteárico, ácido araquidico, ácido behenico, o los correspondientes ácidos insaturados, por ejemplo ácido oleico, ácido elaidico, ácido erucico, ácido brasidico o ácido linoleico, si se desea con la adición de antioxidantes, por ejemplo, vitamina E, \beta-caroteno, o 3,5-di-terc-butil-4-hidroxitolueno. El componente de alcohol de esos ésteres de ácido graso tiene un máximo de 6 átomos de carbono y es mono o polihidrico, por ejemplo un alcohol mono, di, o trihidrico, por ejemplo, metanol, etanol, propanol, butanol, o pentanol o sus isómeros, pero especialmente glicol y glicerol. Los siguientes ejemplos de ésteres de ácido graso son por lo tanto para ser mencionados: etil oleato, isopropil miristato, isopropil palmitato, "Labrafil M 2375" (polioxietileno glicerol trioleato, Gattefossé, Paris), "Labrafil M 1944 CS" (glicéridos poliglicolizados insaturados preparados mediante alcoholisis de aceite kernel de albaricoque y que consiste de glicéridos y éster de polietilenglicol, Gattefossé, Francia), "Labrasol" (glicéridos poliglicolizados saturados preparados por alcoholisis de TCM y que consisten de glicéridos de éster de polietilen glicol, Gattefossé, Francia) y/o "Migliol 812" (triglicérido de ácidos grasos saturados con una cadena larga de C_{8} a C_{12}, Hüls AG, Alemania), pero especialmente aceites vegetales, tales como aceite de semilla de algodón, aceite de almendra, aceite de olivas, aceite de ricino, aceite de sésamo, aceite de fríjol de soya y particularmente aceite de cacahuete.The oil suspensions comprise as the component in oil vegetable, synthetic or semi-synthetic custom for purposes of injection. It can be mentioned as such fatty acid esters especially liquids containing as the acid component a long chain fatty acid that has 8-22, especially 12-22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, acid pentadecyl, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or the corresponding acids unsaturated, for example oleic acid, elaidic acid, acid erucic, brasidic acid or linoleic acid, if desired with the addition of antioxidants, for example, vitamin E, β-carotene, or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is mono or polyhydric, for example a mono, di, or trihydric alcohol, for example, methanol, ethanol, propanol, butanol, or pentanol or its isomers, but especially glycol and glycerol. The following examples of acid esters Fatty are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefossé, Paris), "Labrafil M 1944 CS "(prepared unsaturated polyglycolized glycerides using apricot kernel oil alcoholysis and which consists of glycerides and polyethylene glycol ester, Gattefossé, France), "Labrasol" (prepared saturated polyglycolized glycerides by TCM alcoholysis and consisting of ester glycerides of polyethylene glycol, Gattefossé, France) and / or "Migliol 812" (saturated fatty acid triglyceride with a long chain of C_ {8} to C_ {12}, Hüls AG, Germany), but especially oils vegetables, such as cottonseed oil, oil almond, olive oil, castor oil, sesame oil, soybean oil and particularly peanut oil.
Las composiciones de inyección se preparan como de costumbre bajo condiciones estériles; lo mismo aplica también a suministrar las composiciones en ampollas o frascos, por ejemplo, y sellando los recipientes.Injection compositions are prepared as usually under sterile conditions; the same also applies to supply the compositions in ampoules or bottles, for example, and sealing the containers.
Las composiciones farmacéuticas para administración oral se pueden obtener por ejemplo, al combinar el ingrediente activo con uno o más portadores sólidos, donde granular una mezcla obtenida apropiada, y, si se desea, procesar la mezcla o gránulos, donde se ha apropiado mediante la adición de excipientes adicionales, para dar tabletas o núcleos de tableta recubiertos con azúcar.Pharmaceutical compositions for oral administration can be obtained for example by combining the active ingredient with one or more solid carriers, where granulate an appropriate obtained mixture, and, if desired, process the mixture or granules, where it has been appropriated by the addition of excipients additional, to give tablets or tablet cores coated with sugar.
Los portadores adecuados son especialmente llenadores tales como azucares, por ejemplo lactosa, sacarosa, manitol o sorbitol, preparaciones de celulosa y/o fosfatos de calcio por ejemplo fosfato de tricalcio o hidrogenfosfato de calcio, y también ligadores, tales como almidones, por ejemplo, maíz, trigo, arroz o almidón de papa, metilcelulosa, hidroxipropilmetil celulosa, carboximetil celulosa de sodio y/o polivinilpirrolidona y/o, si se desea, desintegradores, tales como los almidones anteriormente mencionados, también carboximetil almidón, pilivinilpirrolidona reticulada, ácido arginico o sales de éstos, tales como alginato de sodio. Los adjuntos adicionales son principalmente acondicionadores de flujo y lubricantes, por ejemplo ácido salicílico, talco, ácido esteárico o sales de éstos, tales como estearato de magnesio o calcio, y/o polietilen glicol, o derivados de éstos.Suitable carriers are especially fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates for example tricalcium phosphate or calcium hydrogen phosphate, and also linkers, such as starches, for example, corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrators, such as starches above mentioned, also carboxymethyl starch, cross-linked pilivinylpyrrolidone, arginic acid or salts thereof, such as sodium alginate. Additional attachments are mainly flow conditioners and lubricants, for example salicylic acid, talc, stearic acid or salts thereof, such such as magnesium or calcium stearate, and / or polyethylene glycol, or derivatives thereof.
Los núcleos de tableta recubiertos con azúcar se puede suministrar con recubrimientos adecuados opcionalmente entéricos, que utilizan entre otros, soluciones de azúcar concentrada que pueden comprender, goma arábica, talco, polivinilpirrolidona, polietilen glicol y/o dióxido de titanio, o soluciones de recubrimiento en disolventes orgánicos adecuados o mezclas disolventes, o, para la preparación de recubrimientos entéricos, soluciones de preparaciones de celulosa adecuadas, tales como eftalato de acetil celulosa o eftalato de hidroxipropilmetil celulosa. Los tintes o pigmentos se pueden agregar a las tabletas o a los recubrimientos de tableta recubiertos con azúcar, por ejemplo para propósitos de identificación o para indicar las dosis diferentes del ingrediente activo.The sugar-coated tablet cores are can be supplied with suitable coatings optionally enteric, which use sugar solutions among others concentrated they can understand, gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings enteric, solutions of suitable cellulose preparations, such as acetyl cellulose eftalate or hydroxypropylmethyl eftalate cellulose. Dyes or pigments can be added to tablets or to sugar coated tablet coatings, for example for identification purposes or to indicate doses different from the active ingredient.
Las composiciones farmacéuticas oralmente administrables también incluyen cápsulas rellenas en seco que consisten de gelatina, y también cápsulas selladas suaves que consisten de gelatina y un plastificador, tal como glicerol o sorbitol. Las cápsulas rellenas en seco pueden contener el ingrediente activo en la forma de gránulos, por ejemplo como una mezcla de rellenos, tales como almidón de maíz, ligadores y/o deslizantes, tales como talco o estearato de magnesio y, donde sea apropiado estabilizadores. En las cápsulas suaves, el ingrediente activo se disuelve o se suspende preferiblemente en excipientes líquidos adecuados, tales como aceites grasos, aceite de parafina o polietilenglicoles líquidos o ésteres de ácido graso o etileno o propilenglicol, a los cuales se puede agregar estabilizadores y detergentes, por ejemplo del tipo de éster de ácido graso de polioxietileno sorbitan.The pharmaceutical compositions orally administrable also include dry filled capsules that they consist of gelatin, and also soft sealed capsules that consist of gelatin and a plasticizer, such as glycerol or sorbitol. Dry filled capsules may contain the active ingredient in the form of granules, for example as a mixture of fillers, such as corn starch, binders and / or sliders, such as talc or magnesium stearate and, wherever appropriate stabilizers. In soft capsules, the ingredient active dissolves or is preferably suspended in excipients suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols or esters of fatty acid or ethylene or propylene glycol, to which stabilizers can be added and detergents, for example of the fatty acid ester type of polyoxyethylene sorbitan.
Otras formas de administración oral son, por ejemplo, jarabes preparados como de costumbre que comprenden el ingrediente activo, por ejemplo en forma suspendida y en una concentración de aproximadamente 5% a 20%, preferiblemente aproximadamente 10%, o en una concentración similar que suministra una dosis única adecuada, por ejemplo, cuando se administra en mediciones de 5 o 10 ml. También son adecuadas, por ejemplo, concentrados de polvo o líquido para la preparación de agitados, por ejemplo en leche. Tales concentrados también se empacan en cantidades de dosis únicas.Other forms of oral administration are, by example, syrups prepared as usual comprising the active ingredient, for example in suspended form and in a concentration of about 5% to 20%, preferably approximately 10%, or in a similar concentration that supplies a suitable single dose, for example, when administered in 5 or 10 ml measurements. They are also suitable, for example, powder or liquid concentrates for stirring preparation, for example in milk. Such concentrates are also packed in single dose amounts.
Las composiciones farmacéuticas rectalmente
administrables adecuadas son, por ejemplo, supositorios que
consisten de una combinación del ingrediente activo y una base de
supositorio. Las bases de supositorio adecuadas son, por ejemplo,
triglicéridos naturales o sintéticos, hidrocarburos parafínicos
polietilenglicoles o alcanoles supe-
riores.Suitable rectally administrable pharmaceutical compositions are, for example, suppositories consisting of a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, polyethylene glycol paraffinic hydrocarbons or higher alkanols.
riores.
Para la administración parenteral existen soluciones acuosas principalmente adecuadas del ingrediente activo en forma soluble en agua, por ejemplo en la forma de sal soluble en agua o suspensiones de inyección acuosa que contiene sustancias que incrementan la viscosidad, por ejemplo carboximetilcelulosa de sodio, sorbitol y/o dextrano y, si se desea, estabilizadores. El ingrediente activo, donde se ha apropiada junto con los adjuntos, también se puede estar en la forma de un liofilizado y puede ser hecho en una solución antes de la administración parenteral mediante la adición de disolventes adecuados.For parenteral administration there are mainly suitable aqueous solutions of the active ingredient in water soluble form, for example in the form of salt soluble in water or aqueous injection suspensions containing substances that increase the viscosity, for example carboxymethyl cellulose of sodium, sorbitol and / or dextran and, if desired, stabilizers. He active ingredient, where appropriate along with the attachments, it can also be in the form of a lyophilisate and can be made in a solution before parenteral administration by the addition of suitable solvents.
Las soluciones tal como se utilizan, por ejemplo, para la administración parenteral se pueden emplear como soluciones de infusión.The solutions as they are used, by For example, parenteral administration can be used as infusion solutions
Los preservativos preferidos son, por ejemplo, antioxidantes, tales como ácido ascórbico, o microbicidas, tales como ácido sórbico o ácido benzoico.Preferred condoms are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
Los ungüentos son emulsiones de aceite en agua que contienen hasta el 70%, pero preferiblemente 20%-50% de la fase de agua o acuosa. Adecuadas como fase grasosas son principalmente los hidrocarburos, por ejemplo gelatina de petróleo, aceite de parafina y parafinas duras, las cuales, con el fin de mejorar la capacidad de unión al agua, contiene preferiblemente compuestos hidroxi adecuados, tales como alcoholes grasos o ésteres de estos, por ejemplo cetil alcohol o alcoholes de cera de lana, tales como cera de lana. Los emulsificadores son sustancias lipófilas adecuadas, tales como ésteres de ácido graso de sorbitan (Spans) por ejemplo oleato de sorbitan y/o isostearato de sorbitan. Los aditivos a la fase acuosa son, por ejemplo, humectantes, tales como polialcoholes, por ejemplo glicerol, propilenglicol, sorbitol y/o polietilen glicol y son preservativos y perfumes.Ointments are oil in water emulsions containing up to 70%, but preferably 20% -50% of the phase of water or water. Suitable as fatty phase are mainly hydrocarbons, for example petroleum jelly, oil paraffin and hard paraffins, which, in order to improve the water binding capacity, preferably contains compounds suitable hydroxy, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax Emulsifiers are lipophilic substances suitable, such as sorbitan fatty acid esters (Spans) by example sorbitan oleate and / or sorbitan isostearate. The additives to the aqueous phase are, for example, humectants, such as polyols, for example glycerol, propylene glycol, sorbitol and / or Polyethylene glycol and are preservatives and perfumes.
Los ungüentos grasos son anhidros y contiene como base especialmente hidrocarburos, por ejemplo parafina, gelatina de petróleo o parafina o aceite de parafina, también grasas naturales o parcialmente sintéticas, por ejemplo triglicérido de ácido graso de coco, o preferiblemente aceites endurecidos, por ejemplo aceite de cacahuate hidrogenado o aceite de ricino, también ésteres parciales de ácido graso de glicerol, por ejemplo mono y/o distearato de glicerol y también, por ejemplo, los alcoholes grasos que incrementan la absorción de agua, emulsificadores y/o aditivos mencionados en relación con los ungüentos.Fatty ointments are anhydrous and contain as a base especially hydrocarbons, for example paraffin, petroleum jelly or paraffin or paraffin oil, also fats natural or partially synthetic, for example triglyceride of coconut fatty acid, or preferably hardened oils, by example hydrogenated peanut oil or castor oil, also partial esters of glycerol fatty acid, for example mono and / or glycerol distearate and also, for example, fatty alcohols that increase water absorption, emulsifiers and / or additives mentioned in relation to ointments.
Las cremas son emulsiones de aceite en agua que contiene mas del 50% de agua. Como base aceitosa se utilizan principalmente alcoholes grasos, por ejemplo, lauril, cetil o estearil alcohol, ácidos grasos, por ejemplo ácido palmítico o esteárico, ceras liquidas a sólidas, por ejemplo isopropil miristato, cera de lana o cera de abejas y/o hidrocarburos, por ejemplo gelatina de petróleo (petrolato) o aceite de parafina. Los emulsificadores adecuados son sustancias de superficie activa que tienen predominantemente propiedades hidrófilas, tales como emulsificadores no iónicos apropiados, por ejemplo ésteres de ácido grasos de polialcoholes o aductos de óxido de etileno de estos, tales como ésteres de ácido graso de poliglicerol o ésteres de ácido graso de polioxietileno sorbitan (Tweens), y también ésteres de alcohol graso de polioxietileno o ésteres de ácido graso, o emulsificadores iónicos apropiados, tales como sales de metal alcalino o sulfatos de alcohol graso por ejemplo lauril sulfato de sodio, cetil sulfato de sodio o estearil sulfato de sodio, que son utilizados de costumbre en la presencia de alcoholes grasos, por ejemplo cetil alcohol o estearil alcohol. Los aditivos a la fase acuosa son, entre otros, agentes que reducen el secado de las cremas, por ejemplo polialcoholes tales como glicerol, sorbitol, propilenglicol y/o polietilenglicoles y también preservativos y perfumes.Creams are emulsions of oil in water that It contains more than 50% water. As an oily base they are used mainly fatty alcohols, for example, lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic acid or stearic, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax and / or hydrocarbons, by example petroleum jelly (petrolatum) or paraffin oil. The suitable emulsifiers are active surface substances that they have predominantly hydrophilic properties, such as appropriate nonionic emulsifiers, for example acid esters polyol fatty acids or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or acid esters polyoxyethylene sorbitan fatty acid (Tweens), and also esters of polyoxyethylene fatty alcohol or fatty acid esters, or appropriate ionic emulsifiers, such as metal salts alkali or fatty alcohol sulfates for example lauryl sulfate sodium, sodium cetyl sulfate or sodium stearyl sulfate, which are customarily used in the presence of fatty alcohols, by example cetyl alcohol or stearyl alcohol. Additives to the phase aqueous are, among others, agents that reduce the drying of creams, for example polyols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols and also preservatives and perfumes
Las pastas son cremas de ungüentos que tiene constituyentes en polvo que absorben la secreción, tales como óxidos de metal, por ejemplo óxido de titanio u óxido de zinc, también talco y/o silicato de aluminio, cuyo objeto es unir la humedad o las secreciones presentes.Pasta is ointment creams that have powder constituents that absorb secretion, such as metal oxides, for example titanium oxide or zinc oxide, also talc and / or aluminum silicate, whose purpose is to join the moisture or secretions present.
Las espumas se administran desde recipientes presurizados y son emulsiones líquidas de aceite en agua en forma de aerosol; hidrocarburos halogenados, tales como clorofluoro-alcanos inferiores, por ejemplo diclorodifluorometano y diclorotetrafluorometano o preferiblemente hidrocarburos gaseosos no halógenos, aire, N_{2}O o dióxido de carbono son utilizados como gases propulsores. Como fase aceitosa se utilizan, entre otros, aquellas utilizadas en el caso de ungüentos y cremas, y también los aditivos mencionados en relación con esto.Foams are administered from containers pressurized and are liquid emulsions of oil in water in form of aerosol; halogenated hydrocarbons, such as lower chlorofluoro-alkanes, for example dichlorodifluoromethane and dichlorotetrafluoromethane or preferably non-halogen gaseous hydrocarbons, air, N 2 O or carbon dioxide Carbon are used as propellant gases. As an oily phase it use, among others, those used in the case of ointments and creams, and also the additives mentioned in relation to this.
Las tinturas y soluciones usualmente tiene una base etanólica acuosa a la cual se agregan, entre otros, polialcoholes, por ejemplo glicerol, glicoles y/o polietilenglicol, como humectantes para reducir la evaporación, y sustancias que reducen la grasa, tales como ésteres de ácido graso con polietilenglicoles de bajo peso molecular, es decir, sustancias lipófilas que son solubles en la mezcla acuosa, como un reemplazo para la sustancias grasas extraídas de la piel mediante etanol, y si es necesario, otros adjuntos y aditivos.Tinctures and solutions usually have a aqueous ethanolic base to which are added, among others, polyalcohols, for example glycerol, glycols and / or polyethylene glycol, as humectants to reduce evaporation, and substances that reduce fat, such as fatty acid esters with low molecular weight polyethylene glycols, i.e. substances lipophilic that are soluble in the aqueous mixture, as a replacement for fatty substances extracted from the skin by ethanol, and if necessary, other attachments and additives.
La invención también se relaciona con un proceso o con un método para tratar las condiciones patológicas anteriormente mencionadas, especialmente aquellas condiciones que responden a la inhibición de las proteínas quinasas. Los compuestos de fórmula I se pueden administrar como tal o en la forma de composiciones farmacéuticas, profiláctica o terapéuticamente, preferiblemente en una cantidad efectiva contra la enfermedad mencionada, un animal de sangre caliente, por ejemplo un humano, que requiera tal tratamiento, los compuestos especialmente que son utilizados en la forma de composiciones farmacéuticas. En el caso de un peso de cuerpo de aproximadamente 70 kg una dosis diaria de aproximadamente 0.1 g a aproximadamente 5 g, preferiblemente desde aproximadamente 0.5 g a aproximadamente 2 g de un compuesto de la presente invención se administra.The invention also relates to a process. or with a method to treat pathological conditions previously mentioned, especially those conditions that respond to protein kinase inhibition. The compounds of formula I can be administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an effective amount against the disease mentioned, a warm-blooded animal, for example a human, that requires such treatment, especially the compounds that are used in the form of pharmaceutical compositions. In the case of a body weight of approximately 70 kg a daily dose of about 0.1 g to about 5 g, preferably from about 0.5 g to about 2 g of a compound of the The present invention is administered.
Los siguientes ejemplos sirven para ilustrar la invención.The following examples serve to illustrate the invention.
Si no se menciona de otra manera, la proporción de los disolventes uno al otro es dada en partas en volumen (v/v).If not mentioned otherwise, the proportion of the solvents to each other is given in parts by volume (v / v).
Las formas cortas y abreviaturas utilizadas tiene las siguientes definiciones:The short forms and abbreviations used It has the following definitions:
Eluyentes (gradientes):Eluents (gradients):
Gradientes HPLC:HPLC gradients:
Grad_{20} 20% \rightarrow 100% a) en b) durante 20 min.Grad_20% 20% 100% a) in b) for 20 min.
eluyente a): acetonitrilo + 0.05% TFA; eluyente b): agua + 0.05% TFA. Columna (250 x 4.6 mm) empacada con material de fase inversa C_{18} -Nucleosil® (tamaño de partícula promedio 5 \mum, gel de sílice covalentemente derivada con octadecilsilanos, Macherey & Nagel, Düren, Alemania).eluent a): acetonitrile + 0.05% TFA; eluent b): water + 0.05% TFA. Column (250 x 4.6 mm) packed with material C 18 -Nucleosil® reverse phase (average particle size 5 um, silica gel covalently derived with octadecylsilanes, Macherey & Nagel, Düren, Germany).
Detección mediante absorción UV a 254 nm, los tiempos de retención (t_{Ret}) son dados en minutos.Detection by UV absorption at 254 nm, the retention times (t_ {Ret}) are given in minutes.
Tasa de flujo: 1 ml/min.Flow rate: 1 ml / min.
- abs. abs.
- absoluto (anhidro)absolute (anhydrous)
- TLC-R_{f} TLC-R_ {f}
- R_{f} de acuerdo con cromatografía de capa delgadaR f according to chromatography of thin layer
- DEPC DEPC
- dietil pirocarbonatodiethyl pyrocarbonate
- DIPE DIPE
- diisopropil éterdiisopropyl ether
- DMA Dma
- dimetilacetamidadimethylacetamide
- DMF DMF
- dimetilformamidadimethylformamide
- DMPU DMPU
- 1,3-dimetil-3, 4, 5, 6-tetrahidro-2(1H)-pirimidinona1,3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone
- DMSO DMSO
- dimetil sulfóxidodimethyl sulfoxide
- EI-MS EI-MS
- espectroscopia de masa por ionización de impacto de electrónionization mass spectroscopy of electron impact
- FAB-MS FAB-MS
- espectroscopia de masa por bombardeo de átomo rápidobombardment mass spectroscopy of fast atom
- Said Said
- saturadosaturated
- H H
- hora(s)hours)
- HPLC HPLC
- cromatografía liquida de alta presiónhigh pressure liquid chromatography
- HV Hv
- vacío altohigh vacuum
- Min Min
- minuto(s)minute (s)
- MS MS
- espectroscopia de masamass spectroscopy
- RT RT
- temperatura ambienteroom temperature
- RE RE
- evaporador rotatoriorotary evaporator
- m.p. m.p.
- punto de fusiónmelting point
- brine brine
- solución del cloruro de sodio saturadosaturated sodium chloride solution
- TFA TFA
- ácido trifluoro acéticotrifluoro acetic acid
- THF THF
- tetrahidrofuranotetrahydrofuran
- TPTU TPTU
- O-(1,2-dihidro-2-oxo-1-piridil)-N,N,N',N'-tetrametiluronio tetrafluoroboratoO- (1,2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- b b
- ampliolarge
- d d
- dobletedoublet
- j j
- constante de acoplamientocoupling constant
- m m
- multiplotemultiplot
- q that
- cuartetoquartet
- s s
- singletesinglet
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
136.4 mg (0.50 mmol) de 4-(3-cloroanilino)-6-formil-7H-pirrolo[2,3-d] pirimidina y 67 \mul de N-metilpiperazina en 5 ml de metanol, 15 ml de DMPU y 63 \mul de ácido acético son hidrogenados a 50ºC en la presencia de 30 mg de níquel Raney. El catalizador se filtra, el filtrado se evapora y el residuo se disuelve en acetato de etilo y solución de NaHCO_{3} saturada. La fase acuosa separada se extrae dos veces con acetato de etilo; las fases orgánicas se lavan con solución de NaHCO_{3} saturada, 4 veces con agua y solución salina, se seca sobre Na_{2}SO_{4} y se evapora. La cromatografía de columna (SiO_{2}, CH_{2}Cl/metanol = 7:2) y se agita en dietil éter produciendo 4-(34-cloroanilino)-6[(4-metilpiperazin-1-il)metil]-7H-pirrolo[2,3-d]pirimidina; HPLC:t_{Ret}(Grad_{20}) = 7.4; TLC-R _{f}= 0.16 (CH_{2}Cl/metanol = 7:3); FAB-MS: [M+H]^{+} = 357.136.4 mg (0.50 mmol) of 4- (3-Chloroanilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine and 67 µl of N-methylpiperazine in 5 ml of methanol, 15 ml of DMPU and 63 µl of acetic acid are hydrogenated at 50 ° C in the presence of 30 mg Raney nickel. He catalyst is filtered, the filtrate is evaporated and the residue is Dissolve in ethyl acetate and saturated NaHCO3 solution. The Separated aqueous phase is extracted twice with ethyl acetate; the Organic phases are washed with saturated NaHCO3 solution, 4 times with water and saline, dry over Na2SO4 and evaporates Column chromatography (SiO2, CH 2 Cl / methanol = 7: 2) and stirred in diethyl ether to produce 4- (34-Chloroanilino) -6 [(4-methylpiperazin-1-yl) methyl] -7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 7.4; TLC-R f = 0.16 (CH 2 Cl / methanol = 7: 3); FAB-MS: [M + H] + = 357.
El material de partida se obtiene como sigue:The starting material is obtained as follow:
Etapa 1.1: A 0-5ºC, 56.0 g (0.43 mol) de etil 2-amidoacetato [para la preparación ver: Liebigs Ann. Chem., 1561 (1981)] son introducidos inicialmente en 172 ml de 1,3-dimetil-3,4,5,6-tetrahidro-2(1H)-pirimidinona. 56.0 ml (0.45 mol) de etil bromopiruvato se agregan gota a gota en el curso de 30 min y la mezcla se calienta entonces a 60ºC durante 3 h. La solución con reacción café oscura se vierte en 1 litro de agua de hielo y se extrae con 1 litro de acetato de etilo y dos veces con 0.5 litros de acetato de etilo cada vez. Las fases orgánicas se lavan 3 veces con 0.5 litros de agua y 0.5 litros de solución salina, se secan (Na_{2}SO_{4}) y se evaporan. La cromatografía de columna (SiO_{2}, hexano/etil acetato [1:1]) y la cristalización de dietil éter hexano produce 2-amino-3,5-bis(etoxicarbonil)-1H-pirrol; p.f. 147-149ºC; MS (M)^{+} = 226.Stage 1.1: At 0-5 ° C, 56.0 g (0.43 mol) of ethyl 2-amidoacetate [for preparation see: Liebigs Ann. Chem., 1561 (1981)] are initially introduced into 172 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone. 56.0 ml (0.45 mol) of ethyl bromopyruvate are added dropwise over the course of 30 min and the mixture is then heated at 60 ° C for 3 h. The solution with dark brown reaction is poured into 1 liter of ice water and extracted with 1 liter of ethyl acetate and twice with 0.5 liters of ethyl acetate each time. The organic phases are washed 3 times with 0.5 liters of water and 0.5 liters of saline, dried (Na2SO4) and evaporated. Column chromatography (SiO2, hexane / ethyl acetate [1: 1]) and crystallization of diethyl ether hexane yield 2-amino-3,5-bis (ethoxycarbonyl) -1H-pyrrole; mp 147-149 ° C; MS (M) + = 226.
Estado 1.2: Con la exclusión del aire, 51.5 g (227 mmol) de 2-amino-3,5-bis(etoxicarbonil)-1H-pirrol, 455 mmol de formamida, 227 ml de DMF y 113 ml de ácido fórmico se agitan a 140ºC durante 27 h. La suspensión amarilla resultante se enfría a 0-5ºC. El filtrado y lavado con isopropanol y hexano conduce a 6-etoxicarbonil-4-hidroxi-7H-pirrolo[2,3-d]pirimidina: ^{1}H-NMR (DMSO-d_{6}): 13-12 (2 HX), 7.99 y 7.11 (2s, 2H), 4.31 (q, J=7, 2H), 1.32 (t, J=7,3H).State 1.2: With the exclusion of air, 51.5 g (227 mmol) of 2-amino-3,5-bis (ethoxycarbonyl) -1H-pyrrole, 455 mmol of formamide, 227 ml of DMF and 113 ml of formic acid are stir at 140 ° C for 27 h. The resulting yellow suspension is cooled to 0-5 ° C. Filtering and washing with isopropanol and hexane leads to 6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine: 1 H-NMR (DMSO-d 6): 13-12 (2 HX), 7.99 and 7.11 (2s, 2H), 4.31 (q, J = 7, 2H), 1.32 (t, J = 7.3H).
Etapa 1.3: Bajo una atmósfera de N_{2}, 32.0 g (154 mmol) de 6-etoxicarbonil-4-hidroxi-7H-pirrolo[2,3-d]pirimidina se suspenden en 308 ml (338 mmol) de POCl_{3} a TA y se calientan a 120ºC con agitación; el sólido se disuelve en el curso de esto. Después de agitar a 120ºC durante 3 h, el exceso de POCl_{3} se destila (65ºC de temperatura externa; 15 mbar). La suspensión del residuo en 50 ml de hielo-tolueno frío, filtración y lavado con tolueno produce 4-cloro-6-etoxicarbonil-7H-pirrolo[2,3-d]pirimidina; p.f. 219-221ºC; ^{1}H-NMR (DMSO-d_{6}): 8.77 y 7.24 (2s, 2H), 4.39 (q, J=7, 2H), 1.36 (t, J=7,3H). El producto adicional se puede obtener del filtrado evaporado al agitar en acetato de etilo/agua.Stage 1.3: Under an atmosphere of N 2, 32.0 g (154 mmol) of 6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine they are suspended in 308 ml (338 mmol) of POCl3 at RT and heated at 120 ° C with stirring; The solid dissolves in the course of this. After stirring at 120 ° C for 3 h, excess POCl 3 is distillate (65 ° C external temperature; 15 mbar). The suspension of residue in 50 ml of cold ice-toluene, filtration and washing with toluene produces 4-Chloro-6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine; m.p. 219-221 ° C; 1 H-NMR (DMSO-d_ {6}): 8.77 and 7.24 (2s, 2H), 4.39 (q, J = 7, 2H), 1.36 (t, J = 7.3H). The additional product can be obtained from filtrate evaporated on stirring in ethyl acetate / water.
Etapa 1.4: Bajo una atmósfera de argón, 29.0 g (128 mmol) de 4-cloro-6-etoxicarbonil-7H-pirrolo[2,3-d]pirimidina y 18.0 ml (171 mmol) de 3-cloroanilina en 430 ml de n-butanol se agitan a 100ºC durante 3 h (casi disuelto después de 1 h, luego se forma una suspensión espesa). 400 ml de isopropanol/hexano (1:1) se agregan entonces a la mezcla de reacción enfriada a = 50ºC, y el producto se filtra y se lava con isopropanol y hexano. La agitación en dietil éter produce 4-(3-cloroanilino)-6-etoxicarbonil-7H-pirrolo[2,3-d]pirimidina; ^{1}H-NMR (DMSO-d_{6}): 13.0 y 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1 H), 7.78 (dm, J=8, 1 H), 7.76 (s, 1 H), 7.45 (t, J=8, 1 H), 7.21 (dm, J=8), 1H), 4.37 (q, J=7, 2H), 1.37 (t, J=7,3H).Stage 1.4: Under an argon atmosphere, 29.0 g (128 mmol) of 4-Chloro-6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine and 18.0 ml (171 mmol) of 3-chloroaniline in 430 ml of n-butanol is stirred at 100 ° C for 3 h (almost dissolved after 1 h, then a thick suspension is formed). 400 ml of isopropanol / hexane (1: 1) are then added to the mixture of reaction cooled to = 50 ° C, and the product is filtered and washed with Isopropanol and hexane. Stirring in diethyl ether produces 4- (3-Chloroanilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine; 1 H-NMR (DMSO-d 6): 13.0 and 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1 H), 7.78 (dm, J = 8, 1 H), 7.76 (s, 1 H), 7.45 (t, J = 8, 1 H), 7.21 (dm, J = 8), 1H), 4.37 (q, J = 7, 2H), 1.37 (t, J = 7.3H).
Estado 1.5: Bajo una atmósfera de N_{2}, 1.4 g
(37 mmol) de hidruro de litio aluminio se agregan en porciones a
5.70 g (18 mmol) de
4-(3-cloroanilino)-6-etoxicarbonil-7H-pirrolo[2,3-d]pirimidina.
Después de agitar a 50ºC durante 2 h, se agregan 100 ml de agua
gota a gota a la mezcla de reacción y se filtran a través de Celita.
Se agrega agua al filtrado y la mezcla se extrae 3 veces con
acetato de etilo. Las fases orgánicas se lavan 3 veces con agua y
solución salina, se secan (MgSO_{4}) y se evaporan. La
recristalización proveniente de isopropanol produce
4-(3-cloroanilino)-6-hidroximetil-7H-pirrolo[2,3-d]pirimidina;
HPLC:t_{Ret}(Grad_{20}) = 8.2;
TLC-R_{f} = 0.11 (CH_{2}Cl/metanol [10:1]);
MS:
(M)^{+} = 274.State 1.5: Under an atmosphere of N2, 1.4 g (37 mmol) of lithium aluminum hydride are added in portions to 5.70 g (18 mmol) of 4- (3-chloroanilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine. After stirring at 50 ° C for 2 h, 100 ml of water are added dropwise to the reaction mixture and filtered through Celite. Water is added to the filtrate and the mixture is extracted 3 times with ethyl acetate. The organic phases are washed 3 times with water and saline, dried (MgSO4) and evaporated. Recrystallization from isopropanol produces 4- (3-chloroanilino) -6-hydroxymethyl-7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 8.2; TLC-R f = 0.11 (CH 2 Cl / methanol [10: 1]); MS:
(M) + = 274.
Etapa 1.6: Con enfriamiento con hielo, 1.9 g de dióxido de manganeso (85%) se agrega a una suspensión de 715 mg (2.6 mmol) de 4-(3-cloroanilino)-6-hidroximetil-7H-pirrolo[2,3-d]pirimidina en 170 ml de cloruro de metileno y la mezcla se agita a TA durante 20 h. 20 ml de 1,3-dimetil-3,4,5,6-tetrahidro-2(1H)-pirimidinona (DMPU) se agregan entonces a la mezcla de reacción, y ésta se agita durante 1 h y luego se filtran a través de Hyflo. El residuo de filtración se agita de nuevo (1 h) en 50 ml de cloruro de metileno/DMPU (1:1) y de nuevo se filtra. Los dos filtrados se combinan, se evaporan y se toman en acetato de etilo/THF y agua. Las fases acuosas se extraen dos veces con acetato de etilo; las fases orgánicas se lavan 4 veces con agua y solución salina, se secan (MgSO_{4}) y se evaporan hasta un volumen residual de 20 ml. La adición de dietil éter y la filtración producen 4-(3-cloroanilino)-6-formil-7H-pirrolo[2,3-d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 10.1; TLC-R_{f} = 0.24 (CH_{2}Cl_{2}/metanol [10:1]).Stage 1.6: With ice cooling, 1.9 g of Manganese dioxide (85%) is added to a 715 mg suspension (2.6 mmol) of 4- (3-Chloroanilino) -6-hydroxymethyl-7H-pyrrolo [2,3-d] pyrimidine in 170 ml of methylene chloride and the mixture is stirred at RT for 20 h. 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU) is then added to the reaction mixture, and it is stirred for 1 h and then filtered through Hyflo. The residue of filtration is stirred again (1 h) in 50 ml of chloride methylene / DMPU (1: 1) and again filtered. The two filtered are combine, evaporate and are taken in ethyl acetate / THF and water. The aqueous phases are extracted twice with ethyl acetate; the phases organic washed 4 times with water and saline, dried (MgSO4) and evaporate to a residual volume of 20 ml. The addition of diethyl ether and filtration produce 4- (3-Chloroanilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 10.1; TLC-R f = 0.24 (CH 2 Cl 2 / methanol [10: 1]).
109 mg (0.40 mmol) de
4-(3-cloroanilino)-6-formil-7H-pirrolo[2,3-d]pirimidina
(etapa 1.6) y 70 \mul (0.8 mmol) de morfolino en 6 ml de metanol,
2 ml de DMPU y 50 \mul de ácido acético y se calientan a 50ºC
durante 2 h. 30 mg de níquel Raney se agregan entonces a la mezcla y
se hidrogenan a 50ºC. El catalizador se filtra, el filtrado se
evapora y el residuo se disuelve en acetato de etilo y solución de
Na_{2}CO_{3} saturada. La fase acuosa se separa y se extrae dos
veces con acetato de etilo; las fases orgánicas se lavan con
solución de NaHCO_{3} saturado, dos veces con agua y solución
salina, se secan (MgSO_{4}) y se evaporan. El residuo se toma en
metanol, y la solución se trata con gel de sílice y se secan. El
polvo se agrega a la columna de gel de sílice y se eluye con
CH_{2}Cl_{2}/metanol = 10:1. La cristalización de acetato de
etilo/dietil éter/hexano produce
4-(3-cloroanilino)-6-[)morfolin-4-il)-metil]-7H-pirrolo[2,3-d]pirimidina;
p.f: 244-246ºC; HPLC t_{Ret}(Grad_{20})
= 7.4; TLC-R_{f} = 0.20 (CH_{2}Cl_{2}/metanol
10:1) FAB-MS:
(M+H)^{+} = 344.109 mg (0.40 mmol) of 4- (3-chloroanilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine (step 1.6) and 70 µL (0.8 mmol) of morpholino in 6 ml of methanol, 2 ml of DMPU and 50 µl of acetic acid and heated at 50 ° C for 2 h. 30 mg of Raney nickel are then added to the mixture and hydrogenated at 50 ° C. The catalyst is filtered, the filtrate is evaporated and the residue is dissolved in ethyl acetate and saturated Na2CO3 solution. The aqueous phase is separated and extracted twice with ethyl acetate; The organic phases are washed with saturated NaHCO3 solution, twice with water and saline, dried (MgSO4) and evaporated. The residue is taken in methanol, and the solution is treated with silica gel and dried. The powder is added to the silica gel column and eluted with CH2Cl2 / methanol = 10: 1. Crystallization of ethyl acetate / diethyl ether / hexane yields 4- (3-chloroanilino) -6 - [) morpholin-4-yl) -methyl] -7H-pyrrolo [2,3-d] pyrimidine; mp: 244-246 ° C; HPLC t_ {Ret} (Grad_ {20}) = 7.4; TLC-R f = 0.20 (CH 2 Cl 2 / methanol 10: 1) FAB-MS:
(M + H) + = 344.
115 mg (1.66 mmol de cloruro de hidroxilamonio y
139 mg (1.69 mmol) de acetato de sodio en 2 ml de agua se agregan a
273 mg (1.00 mmol) de
4-(3-cloranilino)-6-formil-7H-pirrolo[2,3-d]pirimidina
(etapa 1.6) en 3 ml de metanol. La suspensión se calienta hasta
ebullir durante 3 h, se enfría y se filtra, y los residuos se lava
con agua/isopro-
panol = 1:1. El producto crudo se disuelve
en aproximadamente 80 ml de THF caliente y se clarifica con carbón
activo. 10 ml de isopropanol se agregan al filtrado y éste se
evapora parcialmente. Los cristales formados en éste proceso se
filtran y se lavan con DIPE y hexano, por medio del cual se obtiene
(E)-4-(3-cloroanilino)-7H-pirrolo-[2,3-d]pirimidina-6-carbaldehido
oxima: ^{1}H-NMR (DMSO-d_{6}):
12.16 y 11.35 (2s, 2HN), 9.60 (s, 1H), 8.35 (s, 1H), 8.19 (sb, 1H),
8.17 (s, 1H), 7.79 (db, J =8, 1H), 7.35 (t, J=8, 1H), 7.05 (db, J=
8, 1H), 7.03 (s, 1H); HPLC: t_{Ret}(Grad_{20}) = 9.5;
FAB-MS: (M+H)^{+} = 288.115 mg (1.66 mmol of hydroxylammonium chloride and 139 mg (1.69 mmol) of sodium acetate in 2 ml of water are added to 273 mg (1.00 mmol) of 4- (3-chloranilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine (step 1.6) in 3 ml of methanol The suspension is heated to boil for 3 h, cooled and filtered, and the residues washed with water / isopro-
panol = 1: 1. The crude product is dissolved in approximately 80 ml of hot THF and clarified with activated carbon. 10 ml of isopropanol are added to the filtrate and it is partially evaporated. The crystals formed in this process are filtered and washed with DIPE and hexane, whereby (E) -4- (3-chloroanilino) -7H-pyrrolo- [2,3-d] pyrimidine-6-carbaldehyde is obtained oxime: 1 H-NMR (DMSO-d 6): 12.16 and 11.35 (2s, 2HN), 9.60 (s, 1H), 8.35 (s, 1H), 8.19 (sb, 1H), 8.17 ( s, 1H), 7.79 (db, J = 8, 1H), 7.35 (t, J = 8, 1H), 7.05 (db, J = 8, 1H), 7.03 (s, 1H); HPLC: t_ {Ret} (Grad_ {20}) = 9.5; FAB-MS: (M + H) + = 288.
Después de la adición de dietiléter y permitiendo que permanezcan a -20ºC, (Z)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidino-6-carbaldehido oxima cristaliza el licor madre evaporado como una mezcla con = 10% de el (E) isómero: ^{1}H-NMR (DMSO-d_{6}): 12.00 (s, 2HN), 9.71 (s, 1H), 8.39 (s, 1H), 8.24 (sb, 1H), 7.84 (db, J=8, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.35 (t, J=8, 1H), 7.05 (db, J=8, 1H); HPLC: t_{Ret}(Grad_{20}) = 9.1; FAB-MS: (M + H)^{+} = 288.After the addition of diethyl ether and allowing them to remain at -20ºC, (Z) -4- (3-Chloroanilino) -7H-pyrrolo [2,3-d] pyrimidino-6-carbaldehyde oxime crystallizes the evaporated mother liquor as a mixture with = 10% of the (E) isomer: 1 H-NMR (DMSO-d_ {6}): 12.00 (s, 2HN), 9.71 (s, 1H), 8.39 (s, 1H), 8.24 (sb, 1H), 7.84 (db, J = 8, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.35 (t, J = 8, 1H), 7.05 (db, J = 8, 1H); HPLC: t_ {Ret} (Grad_ {20}) = 9.1; FAB-MS: (M + H) + = 288.
69.3 mg (0.83 mmol) de clorhidrato de O-metilhidroxilamina y 69.3 mg (0.845 mmol) de acetato de sodio en 1 ml de agua se agregan a 163.3 mg (0.5 mmol) de 4-(3-cloroanilino)-6-formil-7H-pirrolo[2,3-d]pirimidina (etapa 1.6) en 1 ml de metanol. La suspensión se calienta hasta ebullición durante 4h, se enfría y se filtra y el residuo se lava con agua/isopropanol y finalmente dietiléter. 4-(3-Cloroanilino)-7H-pirrolo[2,3-d]pirimidina-6-carbaldehido O-metil oxima se obtiene; HPLC: t_{Ret}(Grad_{20}) = 11.3; TLC-R_{1} = 0.31 (CH_{2}Cl_{2}/metanol 10:1) FAB-MS: (M + H)^{+} = 302.69.3 mg (0.83 mmol) of hydrochloride O-methylhydroxylamine and 69.3 mg (0.845 mmol) of Sodium acetate in 1 ml of water is added to 163.3 mg (0.5 mmol) from 4- (3-Chloroanilino) -6-formyl-7H-pyrrolo [2,3-d] pyrimidine (step 1.6) in 1 ml of methanol. The suspension is heated until boil for 4h, cool and filter and the residue is washed with water / isopropanol and finally diethyl ether. 4- (3-Chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine-6-carbaldehyde O-methyl oxime is obtained; HPLC: t_ {Ret} (Grad_ {20}) = 11.3; TLC-R1 = 0.31 (CH 2 Cl 2 / methanol 10: 1) FAB-MS: (M + H) + = 302.
168.5 mg (0.53 mmol) de 4-(3-cloroanilino)-6-etoxicarbonil-7H-pirrolo [2, 3-d]pirimidina (etapa 1.4) en 3 ml de morfolino se agitan a 50ºC durante 5 días y 100ºC durante un día. La gel de sílice se agrega a la mezcla de reacción, ésta se evapora y el polvo resultante se aplica a la columna de gel de sílice y se eluye con etanol/cloruro de metileno 1:15. Habitando el producto de reacción en isopropanol se conduce a 4-(3-clroroanilino)-6-(morfolin-4-il-carbonil)-7H-pirrolo [2,3 d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 9.2; TLC R_{f} = 0.56 (CH_{2}Cl_{2}/metanol = 10:1); MS (M)^{+} = 357.168.5 mg (0.53 mmol) of 4- (3-Chloroanilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine (step 1.4) in 3 ml of Morpholino is stirred at 50 ° C for 5 days and 100 ° C for one day. The silica gel is added to the reaction mixture, it is evaporated and The resulting powder is applied to the silica gel column and elute with ethanol / methylene chloride 1:15. Inhabiting the product of reaction in isopropanol leads to 4- (3-Chloroanilino) -6- (morpholin-4-yl-carbonyl) -7H-pyrrolo [2,3 d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 9.2; TLC R f = 0.56 (CH 2 Cl 2 / methanol = 10: 1); MS (M) + = 357.
98 mg (0.3 mmol) de TPTU, seguido por 133 \mul (1.2 mmol) de N-metilpiperazina en 1 ml de DMF (\rightarrow solución) se agregan a una suspensión de 97.6 mg (0.30 mmol) de 6-carboxi-4-(3-cloroanilino)-7H-pirrolo [2,3-d]pirimidina en 7 ml de DMF. Después de 1 h, 30 mg adicionales de TPTU se agregan y la mezcla se agita durante toda la noche a TA. La mezcla de reacción se evapora en un HV y el residuo se trata con etanol/cloruro de metileno (1:2) y finalmente con aproximadamente 4 ml de etanol/agua (3:1). 4-(3-cloroanilino)-6-[(4-metilpiperazin-1-il)carbonil]-7H-pirrolo[2,3-dpirimidina cristaliza en éste proceso y se filtra y se lava con etanol/agua (1:1) e isopropanol/hexano (1:1); p.f. 276-278ºC; HPLC: t_{Ret}(Grad_{20}) = 7.3; TLC-R_{f} = 0.21 (CH_{2}Cl_{2}/etanol = 2:1); MS: (M)^{+} = 370.98 mg (0.3 mmol) of TPTU, followed by 133 µl (1.2 mmol) of N-methylpiperazine in 1 ml of DMF (→ solution) are added to a suspension of 97.6 mg (0.30 mmol) of 6-carboxy-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine in 7 ml of DMF. After 1 h, an additional 30 mg of TPTU are added and the mixture is stirred overnight at TA. The reaction mixture is evaporated in a HV and the residue is treated with ethanol / methylene chloride (1: 2) and finally with approximately 4 ml of ethanol / water (3: 1). 4- (3-Chloroanilino) -6 - [(4-methylpiperazin-1-yl) carbonyl] -7H-pyrrolo [2,3-dpyrimidine crystallizes in this process and is filtered and washed with ethanol / water (1: 1) and isopropanol / hexane (1: 1); m.p. 276-278 ° C; HPLC: t_ {Ret} (Grad_ {20}) = 7.3; TLC-R f = 0.21 (CH 2 Cl 2 / ethanol = 2: 1); MS: (M) + = 370.
El material de partida se obtiene como sigue;The starting material is obtained as follow;
Etapa 9.1: Una solución de 25 mg (0.6 mmol) de LiOH. H_{2}O en 0.4 ml de H_{2}O se agrega gota a gota a una suspensión de 95 mg (0.30 mmol) de 4-(3-cloroanilino)-6-etoxicarbonil-7H-pirrolo [2,3-d]pirimidina (ver etapa 1.4) en 0.7 ml de metanol y la mezcla se calienta hasta ebullición durante 4.5 h. Esta se enfría en una baño de hielo y se acidifica con 0.6 ml de solución HCl 1 normal. El filtrado y lavado con agua producen 6-carboxi-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 8.7; FAB-MS: (M + H)^{+} = 289.Stage 9.1: A solution of 25 mg (0.6 mmol) of LiOH H2O in 0.4 ml of H2O is added dropwise to a 95 mg suspension (0.30 mmol) of 4- (3-Chloroanilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine (see step 1.4) in 0.7 ml of methanol and the mixture is heated until boiling for 4.5 h. It is cooled in an ice bath and acidified with 0.6 ml of normal HCl 1 solution. Filtering and washing with water produce 6-carboxy-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 8.7; FAB-MS: (M + H) + = 289.
144 mg (0.50 mmol) de 6-aminocarbonil-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidina y 202 mg (0.5 mmol) de reactivo de Lawesson's en 5 ml de THF se calientan hasta ebullición durante 17 h y la mezcla entonces se evapora. Cromatografía de columna (SiO_{2}, CH_{2}Cl_{2}/etanol = 15:1) del residuo y agitada en dietiléter produce 4-(3-cloroanilino)-6-(tiocarbamoil)-7H-pirrolo[2,3-d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 9.8; TLC-R_{f} = 0.44 (CH_{2}Cl_{2}/metanol = 10:1); FAB-MS: (M+H)^{+} = 304; IR: (KBr) inter alia 1614s, 1566s, 1506m, 1474s, 1380m, 1354m, 1294m, 1134m.144 mg (0.50 mmol) of 6-aminocarbonyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine and 202 mg (0.5 mmol) of Lawesson's reagent in 5 ml of THF are heated to boil for 17 h and the mixture is then evaporated. Column chromatography (SiO2, CH2Cl2 / ethanol = 15: 1) of the residue and stirred in diethyl ether produces 4- (3-chloroanilino) -6- (thiocarbamoyl) -7H-pyrrolo [2 , 3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 9.8; TLC-R f = 0.44 (CH 2 Cl 2 / methanol = 10: 1); FAB-MS: (M + H) + = 304; IR: (KBr) inter alia 1614 s , 1566 s , 1506 m , 1474 s , 1380 m , 1354 m , 1294 m , 1134 m .
El material de partida se obtiene como sigue:The starting material is obtained as follow:
Etapa 10.1: 90 mg (0.285 mmol) de 4-(3-cloroanilino)-6-etoxicarbonil-7H-pirrolo[2,3-d]pirimidina (etapa 1.4) en 30 ml de metanol y = 5 mg de amonio se calientan a 120ºC durante 48 h en un autoclave. La mezcla de reacción se trata con gel de sílice, se evapora, se aplica a la columna de gel de sílice como un polvo y finalmente se eluye con cloruro de metileno/metanol/THF (210:35: 10). La filtración con metanol a través de una columna de alúmina (básica) y agitando en acetato de etilo produce 6-aminocarbonil-4-(3-cloroanilino)-7H-pirrolo [2,3-d]pirimidina; HPLC: t_{ Ret}(Grad_{20}) = 8.1; TLC-R_{f} = 0.18 (CH_{2}Cl_{2}/metanol = [10:1]); alta resolución MS: (M+H)^{+} = 288.0669 (calc. 288.0652).Stage 10.1: 90 mg (0.285 mmol) of 4- (3-Chloroanilino) -6-ethoxycarbonyl-7H-pyrrolo [2,3-d] pyrimidine (step 1.4) in 30 ml of methanol and = 5 mg of ammonium are heated to 120 ° C for 48 h in an autoclave. The reaction mixture is treated. with silica gel, it evaporates, it is applied to the gel column of silica as a powder and finally eluted with chloride methylene / methanol / THF (210: 35: 10). Filtration with methanol at through a column of alumina (basic) and stirring in acetate ethyl produces 6-aminocarbonyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ { Ret} (Grad_ {20}) = 8.1; TLC-R_ {f} = 0.18 (CH 2 Cl 2 / methanol = [10: 1]); high resolution MS: (M + H) + = 288.0669 (calc. 288.0652).
El material de partida se obtiene alternativamente y ventajosamente como sigue:The starting material is obtained alternatively and advantageously as follows:
Etapa alternativa 10.1: Una mezcla de 2.165 g (7.5 mmol) de 6-carboxi-4-(3-cloro-anilino)-7H-pirrolo [2,3-d]pirimidina en 60 ml de THF y 10 ml de DMPU se calientan bajo reflujo durante 30 min y luego se enfrían a 0ºC, luego de lo cual se obtiene una suspensión fina. 824 \mul (7.5 mmol) de N-metilmorfolino seguido por 981 \mul (7.5 mmol) de isobutil cloroformato en 10 ml de THF y después 1 h a 0ºC, 824 \mul (7.5 mmol) de N-metilmorfolino seguido por 981 \mul (7.5 mmol) de isobutil cloroformato se agregan de nuevo gota a gota. La mezcla se agita durante 1 h y luego se agrega gota a gota a 70 ml de una solución saturada de amonio en dioxano. Después de 3 h, la mezcla se concentró in vacuo. El residuo se vertió en agua, y el precipitado se filtró y se lavó con agua e isopropanol hirviente, luego de lo cual se obtuvo 6- aminocarbonil-4-(3-cloroanilino)-7H-pirrolo [2,3-d]pirimidina. Se obtuvo un producto adicional del filtrado de isopropanol.Alternative stage 10.1: A mixture of 2,165 g (7.5 mmol) of 6-carboxy-4- (3-chloro-anilino) -7H-pyrrolo [2,3-d] pyrimidine in 60 ml of THF and 10 ml of DMPUs are heated under reflux for 30 min and then cooled to 0 ° C, after which a fine suspension is obtained. 824 \ mul (7.5 mmol) of N-methylmorpholino followed by 981 µl (7.5 mmol) of isobutyl chloroformate in 10 ml of THF and then 1 h at 0 ° C, 824 µl (7.5 mmol) of N-methylmorpholino followed by 981 µl (7.5 mmol) of isobutyl chloroformate are added again drop by drop. Mix stir for 1 h and then add dropwise to 70 ml of a saturated solution of ammonium in dioxane. After 3 h, the mixture concentrated in vacuo. The residue was poured into water, and the precipitate was filtered and washed with water and boiling isopropanol, after which 6- aminocarbonyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine. A product was obtained additional isopropanol filtrate.
57.5 mg (0.19 mmol) de 4-(3-cloroanilino)-6-(tiocarbamoil)-7H-pirrolo[2,3-d]pirimidina (ver ejemplo 10) en 3 ml de metanol y 57.3 mg (0.25 mmol) de 4-metoxifenacil bromuro se calientan hasta ebullición durante 17 h. Enfriando la suspensión amarilla pálida, filtrando y lavando con isopropanol/dietiléter se produce 4-(3-cloroanilino)-6-[4-(4-metoxifenil)tiazol-2-il]-7H-pirrolo[2,3-d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 15.4; TLC-R_{f} = 0.33 (CH_{2}Cl_{2}/metanol = 10:1); FAB-MS: (M+H)^{+} = 434.57.5 mg (0.19 mmol) of 4- (3-Chloroanilino) -6- (thiocarbamoyl) -7H-pyrrolo [2,3-d] pyrimidine (see example 10) in 3 ml of methanol and 57.3 mg (0.25 mmol) of 4-methoxyphenacyl bromide is heated until boil for 17 h. Cooling the pale yellow suspension, filtering and washing with isopropanol / diethyl ether occurs 4- (3-Chloroanilino) -6- [4- (4-methoxyphenyl) thiazol-2-yl] -7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 15.4; TLC-R f = 0.33 (CH 2 Cl 2 / methanol = 10: 1); FAB-MS: (M + H) + = 434.
57.5 mg (0.19 mmol) de 4-(3-cloroanilino)-6-(tiocarbamoil)-7H-pirrolo[2,3-d]pirimidina (ver ejemplo 10) y 34 ml de 1-bromo-2-butanona (Aldrich; Milwaukee/USA) en 3 ml de dioxano se calientan hasta ebullición durante 2 h. Enfriando, filtrando la suspensión y lavando con isopropanol/dietiléter se produce 4-(3-cloroanilino)-6-(4-etiltiazol-2-il)-7H-pirrolo[2,3-d]pirimidina HPLC: t_{Ret}(Grad_{20}) = 13.6; FAB-MS: (M+H)^{+} = 356.57.5 mg (0.19 mmol) of 4- (3-Chloroanilino) -6- (thiocarbamoyl) -7H-pyrrolo [2,3-d] pyrimidine (see example 10) and 34 ml of 1-Bromo-2-Butanone (Aldrich; Milwaukee / USA) in 3 ml of dioxane are heated until boil for 2 h. Cooling, filtering the suspension and washing with isopropanol / diethyl ether occurs 4- (3-Chloroanilino) -6- (4-ethylthiazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine HPLC: t_ {Ret} (Grad_ {20}) = 13.6; FAB-MS: (M + H) + = 356.
4-(3-cloroanilino)-6-(4.5-dimetiltiazol-2-il)-7H-pirrolo[2,3-d]pirimidina se obtiene mediante el proceso descrito en éste texto.4- (3-Chloroanilino) -6- (4,5-dimethylthiazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine It is obtained by the process described in this text.
19 mg (0.45 mmol) de cloro de litio y 19.5 mg (0.30 mmol) de ácida de sodio se agregan a una solución de de 80.9 mg (0.30 mmol) de 4-(3-cloroanilino)-6-ciano-7H-pirrolo[2,3-d]pirimidina en 1 ml de metoxietanol y la mezcla se calienta hasta ebullición durante 6.5 h. La mezcla de reacción se vierte en agua/HCL (conc) 10:1, la mezcla se agita durante 30 min y los sólidos se filtran y se lavan con agua. Disolviendo los cristales en THF/isopropanol, evaporación parcial hasta cristalización, filtrado y lavado con dietiléter logra 4-(3-cloroanilino)-6-(tetrazol-5-il)-7H-pirrolo[2,3-d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 9.5; TLC-R_{f} = 0.45 (CH_{2}Cl_{2}/metanol = 7:1); FAB-MS: (M+H)^{+} = 313.19 mg (0.45 mmol) of lithium chlorine and 19.5 mg (0.30 mmol) of sodium acid are added to a solution of 80.9 mg (0.30 mmol) of 4- (3-Chloroanilino) -6-cyano-7H-pyrrolo [2,3-d] pyrimidine in 1 ml of methoxyethanol and the mixture is heated to a boil for 6.5 h. The reaction mixture is poured into water / HCL (conc) 10: 1, the mixture is stirred for 30 min and the solids are filtered and They wash with water. Dissolving the crystals in THF / isopropanol, partial evaporation until crystallization, filtering and washing with diethyl ether achieves 4- (3-Chloroanilino) -6- (tetrazol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 9.5; TLC-R f = 0.45 (CH 2 Cl 2 / methanol = 7: 1); FAB-MS: (M + H) + = 313.
El material de partida se obtuvo como sigue:The starting material was obtained as follows:
Etapa 14.1: 13 ml de cloruro de fósforo se agregaron a 1.048 g (3.6 mmol) de 6-aminocarbonil-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidina (ver etapa 10.1) y 0.7 ml de N,N-dimetilacetamida. Después de agitar a TA durante 1 h y a 100ºC durante 4h, la mezcla de reacción se vertió en una solución saturada enfriada con hielo de NaHCO_{3}. La extracción con acetato de etilo (3 veces) lavado con capas organizas con una solución de NaHCO_{3}. Agua y solución de cloruro de sodio saturado, secado (Na_{2}SO_{4}) y concentración conduce a un sólido. La cromatografía de columna (SiO_{2}: acetato de etilo), y agitando el producto crudo en dietiléter y hexano se produce 4-(3-cloroanilino)-6-ciano-7H-pirrolo[2,3-d]pirimidina; p.f. 284-287ºC; TLC-R_{f} =0.71 (CH_{2}Cl_{2}/metanol [10:1]); HPLC: t_{Ret}(Grad_{20}) = 11.8.Step 14.1: 13 ml of phosphorus chloride is added to 1,048 g (3.6 mmol) of 6-aminocarbonyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine (see step 10.1) and 0.7 ml of N, N-dimethylacetamide. After stirring at RT for 1 h and at 100 ° C for 4 h, the mixture of reaction was poured into an ice cold saturated solution of NaHCO 3. Extraction with ethyl acetate (3 times) washed with layers you organize with a solution of NaHCO 3. Water and solution of saturated, dried sodium chloride (Na2SO4) and concentration leads to a solid. Column chromatography (SiO2: ethyl acetate), and stirring the crude product in diethyl ether and hexane is produced 4- (3-Chloroanilino) -6-cyano-7H-pyrrolo [2,3-d] pyrimidine; m.p. 284-287 ° C; TLC-R_ {f} = 0.71 (CH 2 Cl 2 / methanol [10: 1]); HPLC: t_ {Ret} (Grad_ {20}) = 11.8.
50.4 mg (0.60 mmol) de NaHCO_{3} y, a 0-5ºC, 600 \mul (0.60 mmol) de yoduro de metilo (1 M en dioxano) se agregan a 187.6 mg (0.60 mmol) de 4-(3-cloro-anilino)-6-(tetrazol-5-il)-7H-pirrolo[2,3-d]pirimidina (ver ejemplo 14) en 12 ml de DMF. Después de agitar a TA durante 18 h, la mezcla se diluyó con acetato de etilo, un poco de THF y agua y la fase acuosa se separó y se extrajo de nuevo con acetato de etilo y un poco de THF. Las fases orgánicas se lavaron 2 veces con agua y solución salina, se secaron con MgSO_{4} y se evaporaron. Agitando el residuo en THF/etanol se logro una mezcla 2:1 de 4-(3-cloroanilino)-6-(2-metiltetrazol-5-il)-7H-pirrolo[2,3-d]pirimidina y 4-(3-cloroanilino)-6-(1-metiltetrazol-5-il)-7H-pirrolo[2,3-d]pirimidina; HPLC: t_{Ret}(Grad_{20}) = 10.5 (1 part) y 10.7 (2 parts), ^{1}H-NMR (DMSO-d_{6}) inter alias 4.45 (s, 2-H_{3}C-tetrazol), 4.32 (s, 1-H_{3}C-tetrazol); FAB-MS: (M+H)^{+} = 327.50.4 mg (0.60 mmol) of NaHCO3 and, at 0-5 ° C, 600 µL (0.60 mmol) of methyl iodide (1 M in dioxane) are added to 187.6 mg (0.60 mmol) of 4- (3-Chloro-anilino) -6- (tetrazol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine (see example 14) in 12 ml of DMF. After stirring at RT for 18 h, the mixture was diluted with ethyl acetate, a little THF and water and the aqueous phase was separated and extracted again with acetate ethyl and a little THF. The organic phases were washed twice with water and saline, dried with MgSO4 and evaporated. Stirring the residue in THF / ethanol achieved a 2: 1 mixture of 4- (3-Chloroanilino) -6- (2-methyltetrazol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine Y 4- (3-Chloroanilino) -6- (1-methyltetrazol-5-yl) -7H-pyrrolo [2,3-d] pyrimidine; HPLC: t_ {Ret} (Grad_ {20}) = 10.5 (1 part) and 10.7 (2 parts), 1 H-NMR (DMSO-d 6) inter alias 4.45 (s, 2-H 3 C-tetrazol), 4.32 (s, 1-H 3 C-tetrazol); FAB-MS: (M + H) + = 327.
0.1 g (0.304 mmol) de (R)-6-(4-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina y 0.026 ml (0.33 mmol) de metanosulfocloruro en 1 ml de abs. dimetilacetamida se agitan a 0ºC durante 4 h hasta que ya no está presente el material de partida en el TLC. La mezcla de reacción se vierte en 10 ml de agua de hielo. Esta se extrae con acetato de etilo y 20 ml de solución acuosa de NaHCO_{3}. La fase orgánica se lava con agua, se seca y se concentra, (R)-6-(4-sulfonilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina cristaliza. El producto se lava con hexano; p.f. 253-256ºC; FAB-MS: (M + H)^{+} = 408.0.1 g (0.304 mmol) of (R) -6- (4-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine and 0.026 ml (0.33 mmol) of methanesulfochloride in 1 ml of abs. dimethylacetamide is stirred at 0 ° C for 4 h until it is no longer present the starting material in the FTA. The reaction mixture is Pour into 10 ml of ice water. This is extracted with acetate ethyl and 20 ml of aqueous NaHCO3 solution. The organic phase wash with water, dry and concentrate, (R) -6- (4-sulfonylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine crystallizes The product is washed with hexane; m.p. 253-256 ° C; FAB-MS: (M + H) + = 408.
El material de partida se obtiene como sigue:The starting material is obtained as follow:
Etapa 16.1: análogamente en la etapa 19.4, se hierve 6.0 g (220 mmol) de 4-cloro-6-(4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina (ver etapa 19.3) con 6.04 g de (R)-(+)-1-feniletilamina el 120 ml de n-butanol dando (R)-6-(4-nitrofenil-4-[(1-fenilmetil)-amino]- 7H-pirrolo[2,3-d]pirimidina como cristales café óxido de p.f. >250ºC.Stage 16.1: similarly in stage 19.4, it boil 6.0 g (220 mmol) of 4-Chloro-6- (4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine (see step 19.3) with 6.04 g of (R) - (+) - 1-phenylethylamine 120 ml of n-butanol giving (R) -6- (4-nitrophenyl-4 - [(1-phenylmethyl) -amino] - 7H-pyrrolo [2,3-d] pyrimidine as brown oxide crystals of m.p. > 250 ° C.
Etapa 16.2: análogamente a la etapa 19.5, a la reducción de (R)-6-(4-nitrofenil-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina con níquel Raney en THF/metanol da (R)-6-(4-aminofenil-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina; p.f. 234-235ºC; MS: M^{+} = 329.Stage 16.2: analogously to stage 19.5, to the reduction of (R) -6- (4-nitrophenyl-4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine with Raney nickel in THF / methanol gives (R) -6- (4-aminophenyl-4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine; m.p. 234-235 ° C; MS: M + = 329.
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Análogamente al ejemplo 16, lo siguiente se prepara de (R)-6-(4-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina (ver etapa 16.2) y el alquil sulfocloruro apropiado:Similarly to example 16, the following is prepare of (R) -6- (4-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine (see step 16.2) and the appropriate alkyl sulfochloride:
- a)to)
- (R)-6-(4-etilsulfonilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo [2,3-d]pirimidina; p.f. 260-261ºC: FAB MS: (M+H)^{+} = 422, y(R) -6- (4-Ethylsulfonylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine; m.p. 260-261 ° C: FAB MS: (M + H) + = 422, Y
- b)b)
- (R)-6-(4-isopropilsulfonilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina; p.f. 262-263ºC FAB-MS: (M+H)^{+} = 436.(R) -6- (4-Isopropylsulfonylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine; m.p. 262-263 ° C FAB-MS: (M + H) + = 436.
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Análogamente al ejemplo 16, los siguiente se prepara de (R)-6-(3-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina y el alquil sulfocloruro apropiado:Similarly to example 16, the following are prepare of (R) -6- (3-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine and the appropriate alkyl sulfochloride:
- a)to)
- (R)-6-(3-metilsulfonilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina; p.f. 139-148ºC (amorfo); MS: (M^{+}) = 407,(R) -6- (3-Methylsulfonylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine; m.p. 139-148 ° C (amorphous); MS: (M +) = 407,
- b)b)
- (R)-6-(3-etilsulfonilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina; p.f. 235-236ºC;(R) -6- (3-Ethylsulfonylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine; m.p. 235-236 ° C;
- c)C)
- (R)-6-(3-isopropilsulfonilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina; p.f. 257-258ºC; FAB-MS: (M+H)^{+} = 436. (R) -6- (3-Isopropylsulfonylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine; m.p. 257-258 ° C; FAB-MS: (M + H) + = 436.
El material de partida se obtuvo como sigue:The starting material was obtained as follows:
Etapa 18.1: Análogamente al método descrito en la etapa 19.4, se hierve 20. 0 g (700 mmol) de 4-cloro-6-(3-nitrofenil)-7H-pirrolo[2,3-d]-pirimidina (preparados análogamente a las etapas 19.1 a 19.3 ) con 23.1 ml (168 mmol) de (R)-feniletilamina en 23.1 ml de n-butanol que da (R)-6-(3-nitrofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina como cristales café óxido de p. f. >250ºC; MS: M^{+} = 359.Step 18.1: Similar to the method described in step 19.4, 20.0 g (700 mmol) of 4-Chloro-6- (3-nitrophenyl) -7H-pyrrolo [2,3-d] -pyrimidine (prepared analogously to steps 19.1 to 19.3) with 23.1 ml (168 mmol) of (R) -phenylethylamine in 23.1 ml of n-butanol that gives (R) -6- (3-nitrophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine as brown oxide crystals of p. F. > 250 ° C; MS: M + = 359.
Etapa 18.2: Análogamente a la etapa 19.5, la reducción de (R)-6-(3-nitrofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina con níquel Raney en THF/metanol da (R)-6-(3-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina; p.f. 129-190ºC (amorfo); MS: M^{+} = 329.Stage 18.2: Similarly to stage 19.5, the reduction of (R) -6- (3-nitrophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine with Raney nickel in THF / methanol gives (R) -6- (3-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine; m.p. 129-190 ° C (amorphous); MS: M + = 329.
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Análogamente al Ejemplo 16, lo siguiente se preparó de 6-(4-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina y el correspondiente alquil sulfocloruro:Similarly to Example 16, the following is prepared of 6- (4-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine and the corresponding alkyl sulfochloride:
- a)to)
- 6-(4-metilsulfonilaminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina; p.f. >300ºC; FAB-MS: (M+H)^{+} = 414.6- (4-Methylsulfonylaminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 414.
- b)b)
- 4-(3-cloroanilino)-6-(4-etilsulfonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >300ºC; FAB-MS: (M+H)^{+} = 428.4- (3-Chloroanilino) -6- (4-ethylsulfonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 428.
- c)C)
- 4-(3-cloroanilino)-6-(4-isopropilsulfonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >300ºC; FAB-MS: (M+H)^{+} = 442 y4- (3-Chloroanilino) -6- (4-isopropylsulfonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 442 Y
- d)d)
- 4-(3-cloroanilino)-6-(4-fenilsulfonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >300ºC; FAB-MS: (M+H)^{+} = 475.4- (3-Chloroanilino) -6- (4-phenylsulfonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 475.
El material de partida se obtuvo como sigue:The starting material was obtained as follows:
Etapa 19.1: En un recipiente de tres cuellos seco, 75 ml de abs. etanol y 6.5 g (390 mmol) de clorhidrato de etil-2-amidinoacetato [para la preparación ver: Liebigs Ann. Chem., 1895 (1977)] se introducen inicialmente bajo argón, y la mezcla se enfría a 0-5ºC y se trata con 2.65 g (390 mmol) de etóxido de sodio. 5 g (195 mmol) de 2-promo-1-(4-nitrofenil)etan-1-ona se agregan entonces, y la mezcla se le permite llegar a TA y se agita adicionalmente durante 48 h. La mezcla de reacción es luego particionada entre agua y acetato de etilo. La fase de acetato de etilo se lava tres veces con agua y una vez con solución de NaCl, se seca y se filtra, y el filtrado se evapora. El residuo rojo-café se suspende en hexano, 2-amino-3-etoxicarbonil-5-(4-nitrofenil)pirrol precipitando como un producto crudo (pureza 93%) que se utiliza para la siguiente etapa sin purificación adicional. MS: (M)^{+} = 275.Stage 19.1: In a dry three-necked container, 75 ml of abs. ethanol and 6.5 g (390 mmol) of ethyl-2-amidinoacetate hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are initially introduced under argon, and the mixture is cooled to 0-5 ° C and treated with 2.65 g (390 mmol) of sodium ethoxide. 5 g (195 mmol) of 2-promo-1- (4-nitrophenyl) ethan-1-one are then added, and the mixture is allowed to reach RT and further stirred for 48 h. The reaction mixture is then partitioned between water and ethyl acetate. The ethyl acetate phase is washed three times with water and once with NaCl solution, dried and filtered, and the filtrate is evaporated. The red-brown residue is suspended in hexane, 2-amino-3-ethoxycarbonyl-5- (4-nitrophenyl) pyrrole precipitating as a crude product (93% purity) which is used for the next stage without further purification. MS: (M) + = 275.
Etapa 19.2: 2.5 g (97 mmol) de 2-amino-3-etoxicarbonil-5-(4-nitrofenil)pirrol, 19.4 ml de formamida, 9.7 ml de DMF y 3.1 ml de ácido fórmico se agitan a 150ºC juntos durnate 22 h. 1 ml de isopropanol se agrega a la mezcla de reacción caliente. Después de enfriar la mezcla de reacción, el producto precipitado se filtra, éste se lava sucesivamente tres veces con 10 ml de etanol cada vez, dos veces con 10 ml de isopropanol cada vez y dos veces con 10 ml de hexano cada vez. Se obtiene 4-hidroxi-6-(4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina como cristales café óxido que se emplean para la siguiente etapa; MS: (M)^{+} = 256.Step 19.2: 2.5 g (97 mmol) of 2-amino-3-ethoxycarbonyl-5- (4-nitrophenyl) pyrrole, 19.4 ml of formamide, 9.7 ml of DMF and 3.1 ml of formic acid are stir at 150 ° C together for 22 h. 1 ml of isopropanol is added to The hot reaction mixture. After cooling the mixture of reaction, the precipitated product is filtered, it is washed successively three times with 10 ml of ethanol each time, twice with 10 ml of isopropanol each time and twice with 10 ml of hexane each time. Is obtained 4-hydroxy-6- (4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine as brown oxide crystals that are used for the next stage; MS: (M) + = 256.
Etapa 19.3: Al calentar 4-hidroxi-6-(4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina con POCl_{3}, se preparó 4-cloro-6-(4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina (pureza 93%); p.f. >280ºC; FAB-MS: (M+H)^{+} = 275.Stage 19.3: When heating 4-hydroxy-6- (4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine with POCl3, it was prepared 4-Chloro-6- (4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine (purity 93%); m.p. > 280 ° C; FAB-MS: (M + H) + = 275.
Etapa 19.4: Al ebuyir 0.25 g (0.91 mmol) de 4-cloro-6-(4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina con 0.19 ml de 3-cloroanilina en 5 ml de n-butanol, se obtiene 4-(3-cloroanilino)-6-4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina como cristales café óxido; p.f. >250ºC; ^{1}H-NMR (360 Mhz, DMSO-d_{6}): 12.95 (s, pirrol-NH), 10.3 (s, anilina-NH), 8.45 (s, pirimidina-H), 8.24 (s, aromático H), 7.18-8.4 (7 aromático H + pirrol-5H); MS: (M)^{+} = 365.Stage 19.4: When boiling 0.25 g (0.91 mmol) of 4-Chloro-6- (4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine with 0.19 ml of 3-chloroaniline in 5 ml of n-butanol, is obtained 4- (3-Chloroanilino) -6-4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine as brown oxide crystals; m.p. > 250 ° C; 1 H-NMR (360 Mhz, DMSO-d 6): 12.95 (s, pyrrole-NH), 10.3 (s, aniline-NH), 8.45 (s, pyrimidine-H), 8.24 (s, aromatic H), 7.18-8.4 (7 aromatic H + pyrrole-5H); MS: (M) + = 365.
Etapa 19.5: 150 mg (0.41 mmol) de 4-(3-cloroanilina)-6-(4-nitrofenil)-7H-pirrolo[2,3-d]pirimidina son hidrogenados con 50 mg de níquel Raney en 20 ml de THF/metanol a TA y presión normal durante 5 h, el producto deseado precipita en el curso de esto. El catalizador se filtra y el residuo de filtro se lava con THF caliente. El filtrado se evapora hasta sequedad. El producto crudo se purifica al digerir varias veces en metanol y precipitar de THF/hexano, luego de lo cual se obtiene 6-(4-aminofenil)-4-(3-cloroanilina)7H-pirrolo[2,3-d]pirimidina como cristales beige pálido; p.f. >290ºC; ^{1}H-NMR (360 Mhz, DMSO-d_{6}): 12.05 (s, pirrol-NH), 9.38 (s, anilina-NH), 8.31 (s, pirimidina-H), 8.24 (s, aromático H), 7.80 (d, aromático H), 7.53 (d, 2 aromático H), 7.35 (t, aromático H), 7.05 (d, aromático H), 6.90 (s, pirrol-5H), 6.64 (d, 2 aromárico H), 5.35 (s, NH_{2}); MS: (M)^{+} = 335.Stage 19.5: 150 mg (0.41 mmol) of 4- (3-Chloroaniline) -6- (4-nitrophenyl) -7H-pyrrolo [2,3-d] pyrimidine are hydrogenated with 50 mg of Raney nickel in 20 ml of THF / methanol at RT and normal pressure for 5 h, the desired product precipitates in The course of this. The catalyst is filtered and the filter residue is wash with hot THF. The filtrate is evaporated to dryness. He crude product is purified by digesting several times in methanol and precipitate THF / hexane, after which it is obtained 6- (4-aminophenyl) -4- (3-chloroaniline) 7H-pyrrolo [2,3-d] pyrimidine as pale beige crystals; m.p. > 290 ° C; 1 H-NMR (360 Mhz, DMSO-d 6): 12.05 (s, pyrrole-NH), 9.38 (s, aniline-NH), 8.31 (s, pyrimidine-H), 8.24 (s, aromatic H), 7.80 (d, aromatic H), 7.53 (d, 2 aromatic H), 7.35 (t, aromatic H), 7.05 (d, aromatic H), 6.90 (s, pyrrole-5H), 6.64 (d, 2 aromatic H), 5.35 (s, NH2); MS: (M) + = 335.
Análogamente al Ejemplo 16, lo siguiente se preparó de 6-(3-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidina y el correspondiente alquil sulfocloruro:Similarly to Example 16, the following is prepared of 6- (3-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine and the corresponding alkyl sulfochloride:
- a)to)
- 4-(3-cloroanilino)-6-(3-metilsulfonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >300ºC; FAB-MS: (M+H)^{+} = 414.4- (3-Chloroanilino) -6- (3-methylsulfonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 414.
- b)b)
- 4-(3-cloroanilino)-6-(3-etilsulfonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >228-230ºC; FAB-MS: (M+H)^{+} = 428 y4- (3-Chloroanilino) -6- (3-ethylsulfonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 228-230 ° C; FAB-MS: (M + H) + = 428 and
- c)C)
- 4-(3-cloroanilino)-6-(3-isopropilsulfonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >233ºC; FAB-MS: (M+H)^{+} = 442.4- (3-Chloroanilino) -6- (3-isopropylsulfonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 233 ° C; FAB-MS: (M + H) + = 442
El material de partida se obtuvo como sigue:The starting material was obtained as follows:
Etapa 20.1: Análogamente a la etapa 19.4 se hierve 2.0 g (7.28 mmol) de 4-cloro-6-(3-nitrofenil)-7H-pirrolo[2,3-d]-pirimidina con 4.2 ml (40 mmol) de 3-cloroanilina en 150 ml de n-butanol dando 6-(3-nitrofenil-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina como cristales amarillos de p.f. >250ºC; MS: M^{+} = 365.Stage 20.1: Similar to stage 19.4, boil 2.0 g (7.28 mmol) of 4-Chloro-6- (3-nitrophenyl) -7H-pyrrolo [2,3-d] -pyrimidine with 4.2 ml (40 mmol) of 3-chloroaniline in 150 ml of n-butanol giving 6- (3-nitrophenyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine as yellow crystals of m.p. > 250 ° C; MS: M + = 365.
Etapa 20.2: Análogamente a la etapa 19.5, la reducción de 6-(3-nitrofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina con níquel Raney en THF/metanol da 6-(3-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina; p.f. 293-295ºC; MS: M^{+} - 336.Stage 20.2: Similarly to stage 19.5, the reduction of 6- (3-nitrophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine with Raney nickel in THF / methanol gives 6- (3-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. 293-295 ° C; MS: M + - 336.
0.2 g (0.56 mmol) de 6-(4-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver etapa 19.5), 0.097 ml (0.67 mmol) de N,N-dimetilformamida dimetil acetal y 0.112 ml (0.73 mmol)de trietilamina se agitan a TA durante 24 h en 10 ml de THF hasta que todo el material de partida ha desaparecido en el TLC. La solución de reacción se concentra hasta sequedad in vacuo y el residuo se cromatografía sobre una columna de gel de sílice. La cristalización del THF/hexano o etil acetato/hexano da 4-(3-cloroanilino)-6-(4-[dimetilaminometilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. >300ºC; MS: (M)^{+} = 390.0.2 g (0.56 mmol) of 6- (4-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see step 19.5), 0.097 ml (0.67 mmol) of N, N-dimethylformamide dimethyl acetal and 0.112 ml (0.73 mmol) of triethylamine are stirred at RT for 24 h in 10 ml of THF until all the starting material has disappeared in the FTA. The reaction solution is concentrated to dryness in vacuo and the residue is chromatographed on a silica gel column. The crystallization of THF / hexane or ethyl acetate / hexane gives 4- (3-Chloroanilino) -6- (4- [dimethylaminomethylamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; MS: (M) + = 390.
Análogamente al Ejemplo 21, los siguientes compuestos se preparan de 6-(4-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver etapa 19.5) y la correspondiente N,N-dialquilformamida dimetil acetal o heterociclil aldehído dimetil acetal:Similarly to Example 21, the following compounds are prepared from 6- (4-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see step 19.5) and the corresponding N, N-dialkylformamide dimethyl acetal or heterocyclyl dimethyl acetal aldehyde:
- a)to)
- 4-(3-cloroanilino)-6-(4-[dietilaminometilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 310ºC; FAB-MS: (M+H)^{+} = 419,4- (3-Chloroanilino) -6- (4- [diethylaminomethylamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 310 ° C; FAB-MS: (M + H) + = 419,
- b)b)
- 4-(3-cloroanilino)-6-(4[piperidinometilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 300ºC; MS: (M)^{+} = 430,4- (3-Chloroanilino) -6- (4 [piperidinomethylamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; MS: (M) + = 430,
- c)C)
- 4-(3-cloroanilino)-6-(4-[morfolinometilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 310ºC; MS: (M)^{+} = 432, y4- (3-Chloroanilino) -6- (4- [morpholinomethylamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 310 ° C; MS: (M) + = 432, and
- d)d)
- 4-(3-cloroanilino)-6-(4-[(4-metilpiperazino)metilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 310ºC; FAB-MS: (M+H)^{+} = 446.4- (3-Chloroanilino) -6- (4 - [(4-methylpiperazino) methylenamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 310 ° C; FAB-MS: (M + H) + = 446.
Análogamente al Ejemplo 21, los siguientes compuestos se prepararon de 6-(3-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver etapa 20.2) y la correspondiente N,N-dialquilformamida dimetil acetal o morfolinoaldehído dimetil acetal:Similarly to Example 21, the following compounds were prepared from 6- (3-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see step 20.2) and the corresponding N, N-dialkylformamide dimethyl acetal or morpholinoaldehyde dimethyl acetal:
- a)to)
- 4-(3-cloroanilino)-6-(3-[dietilaminometilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 266-268ºC; MS: (M)^{+} = 390,4- (3-Chloroanilino) -6- (3- [diethylaminomethylamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 266-268 ° C; MS: (M) + = 390,
- b)b)
- 4-(3-cloroanilino)-6-(3-[dietilaminometilenamino]-fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 171-172ºC; FAB-MS: (M+H)^{+} = 419, y4- (3-Chloroanilino) -6- (3- [diethylaminomethylamino] -phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 171-172 ° C; FAB-MS: (M + H) + = 419, and
- c)C)
- 4-(3-cloroanilino)-6-(3-[morfolinometilenamino]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 284-286ºC; FAB-MS: (M+H)^{+} = 433.4- (3-Chloroanilino) -6- (3- [morpholinomethylamino] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 284-286 ° C; FAB-MS: (M + H) + = 433.
Análogamente al Ejemplo 21, el siguiente
compuesto se prepara de
(R)-6-(4-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina
(ver etapa 16.2) y N,N-dimetilformamida dimetil
acetal: (R)-6-(4-[dimetilaminome-
tilenamino]fenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina;
p.f. > 300ºC; MS: (M+H)^{+} = 385.Similarly to Example 21, the following compound is prepared from (R) -6- (4-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine (see step 16.2 ) and N, N-dimethylformamide dimethyl acetal: (R) -6- (4- [dimethylaminome-
tilenamino] phenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine; mp> 300 ° C; MS: (M + H) + = 385.
Análogamente al Ejemplo 21, el siguiente
compuesto se prepara de
(R)-6-(3-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina
(ver etapa 18.2) y N,N-dimetilformamida dimetil
acetal: (R)-6-(3-[dimetilamino-
metilenamino]fenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina;
p.f. > 267-269ºC; FAB-MS:
(M+H)^{+} = 385.Similarly to Example 21, the following compound is prepared from (R) -6- (3-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine (see step 18.2 ) and N, N-dimethylformamide dimethyl acetal: (R) -6- (3- [dimethylamino-
methylenamino] phenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine; mp> 267-269 ° C; FAB-MS: (M + H) + = 385.
738 mg (2.02 mmol) de 6-(4-carbonilfenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina se agitan a temperatura ambiente durante 3 h con 3 equivalentes de morfolino y 3.5 equivalentes de DEPC (Aldrich) en DMF. La solución de reacción se vierte sobre agua y el sólido se filtra y se lava con agua y metanol. El producto obtenido se cromatografía sobre gel de sílice y se eluye con cloroformo/metanol/ácido acético/agua (850:130:15:5; v/v). El producto obtenido se digiere en dietil éter, se filtra y se seca. Se obtiene 4-(3-cloroanilino-6-(4-[morfolin-4-il-carbonil]fenil)-7H-pirrolo[2,3-d]-pirimidina en cristales beige; p.f. > 250ºC; FAB-MS: (M+H)^{+} = 434.738 mg (2.02 mmol) of 6- (4-carbonylphenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine stir at room temperature for 3 h with 3 equivalents of morpholino and 3.5 equivalents of DEPC (Aldrich) in DMF. The solution The reaction is poured onto water and the solid is filtered and washed with water and methanol The product obtained is chromatographed on gel silica and elute with chloroform / methanol / acetic acid / water (850: 130: 15: 5; v / v). The product obtained is digested in diethyl ether, filter and dry. Is obtained 4- (3-Chloroanilino-6- (4- [morpholin-4-yl-carbonyl] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine in beige crystals; m.p. > 250 ° C; FAB-MS: (M + H) + = 434.
Análogamente al Ejemplo 26, partiendo de (3-cloroanilino)-6-(4-carbonilfenil)-7H-pirrolo[2,3-d]-pirimidina y N-metilpiperazina 4-(3-cloroanilino)6-(4-[4-metilpiperazin-1-il]-carbonilfenil)-7H-pirrolo[2,3-d]-pirimidina se obtiene; p.f. 250ºC; FAB-MS: (M+H)^{+} = 447.Similarly to Example 26, starting from (3-Chloroanilino) -6- (4-carbonylphenyl) -7H-pyrrolo [2,3-d] -pyrimidine and N-methylpiperazine 4- (3-Chloroanilino) 6- (4- [4-methylpiperazin-1-yl] -carbonylphenyl) -7H-pyrrolo [2,3-d] -pyrimidine is obtained; m.p. 250 ° C; FAB-MS: (M + H) + = 447.
300 mg (0.89 mmol) de 6-(4-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 19.5), disuelta en 20 ml de abs. THF y 2 ml (3.56 mmol) de DMA se tratan con 0.29 ml de etil isocianato (FLUKA) con exclusión de humedad y calentado bajo reflujo hasta que el material de partida ya no está presente en el TLC (24 h). La mezcla de reacción se evaporó hasta sequedad in vacuo y el producto crudo se cromatografía sobre gel de sílice, etil acetato/metanol siendo utilizado como eluyente. Las fracciones que contienen el producto deseado se combinan y se evaporan hasta sequedad. El residuo se disolvió en un poco de THF. El compuesto objetivo se precipitó/cristalizó mediante adición de n-hexano. Se obtuvieron cristales incoloros de 4-(3-cloroanilino)-6-(4-[N^{3}-etilureido]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 290ºC; FAB-MS: (M+H)^{+} = 407.300 mg (0.89 mmol) of 6- (4-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see Step 19.5), dissolved in 20 ml of abs. THF and 2 ml (3.56 mmol) of DMA are treated with 0.29 ml of ethyl isocyanate (FLUKA) excluding moisture and heated under reflux until the starting material is no longer present in the TLC (24 h). The reaction mixture was evaporated to dryness in vacuo and the crude product was chromatographed on silica gel, ethyl acetate / methanol being used as eluent. Fractions containing the desired product are combined and evaporated to dryness. The residue was dissolved in some THF. The target compound was precipitated / crystallized by the addition of n-hexane. Colorless crystals of 4- (3-chloroanilino) -6- (4- [N3 -ethylureido] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine were obtained; mp> 290 ° C; FAB-MS: (M + H) + = 407.
Análogamente al Ejemplo 28, los siguientes compuestos se preparan de 6-(3-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 20.2) y el alquil isocianato correspondiente o fenil isocianato:Similarly to Example 28, the following compounds are prepared from 6- (3-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see Step 20.2) and the corresponding alkyl isocyanate or phenyl isocyanate:
- a)to)
- 4-(3-cloroanilino)-6-(3-[N^{3}-etilureido]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 300ºC; FAB-MS: (M+H)^{+} = 407, y4- (3-Chloroanilino) -6- (3- [N3 -ethylureido] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 407, and
- b)b)
- 4-(3-cloroanilino)-6-(3-[N^{3}-fenilureido]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 300ºC; FAB-MS: (M+H)^{+} = 455.4- (3-Chloroanilino) -6- (3- [N3 -phenylureido] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 455.
Análogamente al Ejemplo 28, se prepara (R)-6-(4-[N^{3}-etilureido]fenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina de (R)-6-(4-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 16...) y etil isocianato; p.f. > 238-240ºC; FAB-MS: (M+H)^{+} = 401.Similarly to Example 28, it is prepared (R) -6- (4- [N3 -ethylureido] phenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine from (R) -6- (4-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine (see Step 16 ...) and ethyl isocyanate; m.p. > 238-240 ° C; FAB-MS: (M + H) + = 401.
Análogamente al Ejemplo 28, (R)-6-(3-[N^{3}-etilureido]-fenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina se prepara de (R)-6-(3-aminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 18.2) y etil isocianato; p.f. > 177-178ºC; FAB-MS: (M+H)^{+} = 401.Similarly to Example 28, (R) -6- (3- [N3 -ethylureido] -phenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine is prepared from (R) -6- (3-aminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine (see Step 18.2) and ethyl isocyanate; m.p. > 177-178 ° C; FAB-MS: (M + H) + = 401.
Análogamente al método descrito en el Ejemplo
28, 300 mg (0.89 mmol) de
6-(4-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina
(ver Etapa 19.5) disuelta en 20 ml de abs. THF y 2 ml de DMA, y
0.27 ml (3.56 mmol) de metil isotiocianato (EGA) dan, después de
re-cristalización de
THF-n-hexano,
4-(3-cloroanilino)-6-(4-[N^{3}-metiltioureido]fenil)-7H-pirrolo[2,3-d]-pirimidina
en la forma de cristales incoloros; p.f. >
275-276ºC; FAB-MS:
(M+H)^{+} = 409.Similarly to the method described in Example 28, 300 mg (0.89 mmol) of 6- (4-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see Step 19.5) dissolved in 20 ml of abs. THF and 2 ml of DMA, and 0.27 ml (3.56 mmol) of methyl isothiocyanate (EGA) give, after re-crystallization of THF-n-hexane, 4- (3-chloroanilino) -6- (4- [N ^ {3} -methylthioureido] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine in the form of colorless crystals; mp> 275-276 ° C; FAB-MS:
(M + H) + = 409.
Análogamente al Ejemplo 32, 6-(3-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina y metil isotiocianato dan 4-(3-cloroanilino)- 6-(3-[N^{3}-metiltioureido]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 198-200ºC; FAB-MS: (M+H)^{+} = 409.Similarly to Example 32, 6- (3-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine and methyl isothiocyanate give 4- (3-chloroanilino) - 6- (3- [N 3 -methylthioureido] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 198-200 ° C; FAB-MS: (M + H) + = 409.
Análogamente al Ejemplo 32, (R)-6-(4-aminofenil)-4-[(1-feniletil)-amino]-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 16.2) y metil isotiocianato dan (R)-6-(3-[N^{3}-metiltioureido]fenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 225-228ºC; FAB-MS: (M+H)^{+} = 403.Similarly to Example 32, (R) -6- (4-aminophenyl) -4 - [(1-phenylethyl) -amino] -7H-pyrrolo [2,3-d] -pyrimidine (see Step 16.2) and methyl isothiocyanate dan (R) -6- (3- [N 3 -methylthioureido] phenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 225-228 ° C; FAB-MS: (M + H) + = 403.
Análogamente al Ejemplo 32, (R)-6-(3-aminofenil)-4-[(1-feniletil)-amino]-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 18.2) y metil isotiocianato dan (R)-6-(3-[N^{3}-metiltioureido]fenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]-pirimidina; p.f. > 188-190ºC; FAB-MS: (M+H)^{+} = 403.Similarly to Example 32, (R) -6- (3-aminophenyl) -4 - [(1-phenylethyl) -amino] -7H-pyrrolo [2,3-d] -pyrimidine (see Step 18.2) and methyl isothiocyanate dan (R) -6- (3- [N 3 -methylthioureido] phenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 188-190 ° C; FAB-MS: (M + H) + = 403.
300 mg (0.89 mmol) de 6-(4-aminofenil-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 19.5), disuelta en 2.7 ml de abs. dioxano y 0.13 ml de 2,6-lutidina, se tratan con una solución de 0.10 ml (0.98 mmol) de metil cloroformato en 1.8 ml de abs. dioxano con la exclusión de humedad y agitada a TA hasta que el material de partida ya no está presente en el TLC. La mezcla de reacción se agregó a 50 ml de agua. Ésta se extrajo entonces con 200 ml de etil acetato y 10 ml de 5% de solución de hidrogen carbonato de sodio acuoso. Las fases de acetato de etilo combinadas se lavaron 3 veces con agua, se secaron y se evaporaron in vacuo. El residuo se cromatografía sobre gel de sílice, eluyendo con cloruro de metileno e incrementando las cantidades de metanol. El compuesto objetivo, 4-(3-cloroanilino)-6-(4-metoxicarbonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina, se cristalizó de metanol o acetona en la forma de cristales coloreados ligeramente de amarillo; p.f. > 300ºC; FAB-MS: (M+H)^{+} = 394.300 mg (0.89 mmol) of 6- (4-aminophenyl-4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see Step 19.5), dissolved in 2.7 ml of dioxane abs and 0.13 ml of 2,6-lutidine, are treated with a solution of 0.10 ml (0.98 mmol) of methyl chloroformate in 1.8 ml of dioxane with the exclusion of moisture and stirred at RT until the starting material is no longer present in TLC The reaction mixture was added to 50 ml of water, which was then extracted with 200 ml of ethyl acetate and 10 ml of 5% aqueous sodium hydrogen carbonate solution.The combined ethyl acetate phases were washed. times with water, dried and evaporated in vacuo.The residue is chromatographed on silica gel, eluting with methylene chloride and increasing the amounts of methanol.The target compound, 4- (3-chloroanilino) -6- (4- methoxycarbonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine, crystallized from methanol or acetone in the form of slightly yellow colored crystals; mp> 300 ° C; FAB-MS: (M + H) + = 394.
Análogamente al Ejemplo 36, los siguientes compuestos se prepararon de 6-(4-aminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]-pirimidina (ver Etapa 19.5) y el correspondiente a alquil cloroformato:Similarly to Example 36, the following compounds were prepared from 6- (4-aminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] -pyrimidine (see Step 19.5) and the corresponding alkyl chloroformate:
- a)to)
- 4-(3-cloroanilino)-6-(4-etoxicarbonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 300ºC; FAB-MS: (M+H)^{+} = 408,4- (3-Chloroanilino) -6- (4-ethoxycarbonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 408,
- b)b)
- 4-(3-cloroanilino)-6-(4-isopropiloxicarbonilaminofenil)-7H-pirrolo[2,3-d]-pirimidina; p.f. > 300ºC; FAB-MS: (M+H)^{+} = 422, y4- (3-Chloroanilino) -6- (4-isopropyloxycarbonylaminophenyl) -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 300 ° C; FAB-MS: (M + H) + = 422, Y
- c)C)
- 4-(3-cloroanilino)-6-{4-[(2-metilpropiloxi)carbonilamino]fenil}-7H-pirrolo[2,3-d]-pirimidina; p.f. > 282-284ºC; FAB-MS: (M+H)^{+} = 436.4- (3-Chloroanilino) -6- {4 - [(2-methylpropyloxy) carbonylamino] phenyl} -7H-pyrrolo [2,3-d] -pyrimidine; m.p. > 282-284 ° C; FAB-MS: (M + H) + = 436.
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3.53 g (9.0 mmol) de 4-(3-cloroanilino)-6-(4-etoxicarbonilfenil)-7H-pirrollo[2,3-d]pirimidina se suspenden en 150 ml de THF. A 54ºC, un total de 0.845 g (21.6 mmol) de hidruro de litio aluminio se introducen en el curso de 5 h. Para trabajar 1 ml de agua, 2 ml de solución de hidróxido de sodio 1 N y 1 ml de agua, seguido por 10 g de sulfato de sodio se agregan sucesivamente. El sólido se filtra y el filtrado se concentra. El residuo obtenido se lava con metanol y dietiléter y luego se seca. 4-(3-cloroanilino)-6-(4-hidroximetilfenil)-7H-pirrollo[2,3-d]pirimidina se obtiene en cristales incoloros; p.f. >250ºC; FAB-MS (M+H)^{+} = 351.3.53 g (9.0 mmol) of 4- (3-Chloroanilino) -6- (4-ethoxycarbonylphenyl) -7H-pyrrollo [2,3-d] pyrimidine they are suspended in 150 ml of THF. At 54 ° C, a total of 0.845 g (21.6 mmol) lithium aluminum hydride are introduced in the course of 5 h. To work 1 ml of water, 2 ml of hydroxide solution 1 N sodium and 1 ml of water, followed by 10 g of sodium sulfate is they add successively. The solid is filtered and the filtrate is concentrate. The obtained residue is washed with methanol and diethyl ether and Then it dries. 4- (3-Chloroanilino) -6- (4-hydroxymethylphenyl) -7H-pyrrollo [2,3-d] pyrimidine it is obtained in colorless crystals; m.p. > 250 ° C; FAB-MS (M + H) + = 351.
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Los siguientes compuestos se obtiene análogamente al proceso descrito en este texto:The following compounds are obtained analogously to the process described in this text:
- a)to)
- (R)-6-(3-benzilaminofenil)-4-[(1-feniletil)amino]-7H-pirrolo[2,3-d]pirimidina; p.f. 253-255ºC.(R) -6- (3-benzylaminophenyl) -4 - [(1-phenylethyl) amino] -7H-pyrrolo [2,3-d] pyrimidine; m.p. 253-255 ° C.
- b)b)
- 6-(4-benziloxi-3-metoxifenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidina; p.f. 237-238ºC.6- (4-benzyloxy-3-methoxyphenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine; m.p. 237-238 ° C.
- c)C)
- 6-(4-benziloxi-3-metoxifenil)-4-(3-metilanilino)-7H-pirrolo[2,3-d]pirimidina; p.f. 231-234ºC.6- (4-benzyloxy-3-methoxyphenyl) -4- (3-methylanilino) -7H-pyrrolo [2,3-d] pyrimidine; m.p. 231-234 ° C.
- d)d)
- 6-(4-hidroxi-3-metoxifenil)-4-(3-metilanilino)-7H-pirrolo[2,3-d]pirimidina; p.f. 234-236ºC.6- (4-hydroxy-3-methoxyphenyl) -4- (3-methylanilino) -7H-pyrrolo [2,3-d] pyrimidine; m.p. 234-236 ° C.
- e)and)
- clorhidrato de 4-anilino-6-(4-hidroxi-3-metoxifenil)-7H-pirrolo[2,3-d]pirimidina; p.f. 242-246ºC.hydrochloride 4-anilino-6- (4-hydroxy-3-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine; m.p. 242-246 ° C.
- f)F)
- clorhidrato de 4-(3-cloroanilino)-6-(4-hidroxi-3-metoxifenil)-7H-pirrolo[2,3-d]pirimidina; p.f. >250ºC.hydrochloride 4- (3-Chloroanilino) -6- (4-hydroxy-3-methoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine; m.p. > 250 ° C.
- g)g)
- 4-(3-cloroanilino)-6-(4-(fur-2-il-carbonilamino]fenil)-7H-pirrolo[2,3-d]pirimidina; p.f. >300ºC.4- (3-Chloroanilino) -6- (4- (fur-2-yl-carbonylamino] phenyl) -7H-pyrrolo [2,3-d] pyrimidine; m.p. > 300 ° C.
- h)h)
- 4-(3-cloroanilino)-6-(4-(tien-2-il-carbonilamino]fenil)-7H-pirrolo[2,3-d]pirimidina; p.f. >300ºC.4- (3-Chloroanilino) -6- (4- (tien-2-yl-carbonylamino] phenyl) -7H-pyrrolo [2,3-d] pyrimidine; m.p. > 300 ° C.
- i)i)
- 6-(4-benzilaminofenil)-4-(3-cloroanilino)-7H-pirrolo[2,3-d]pirimidina; p.f. > 300ºC.6- (4-benzylaminophenyl) -4- (3-chloroanilino) -7H-pyrrolo [2,3-d] pyrimidine; m.p. > 300 ° C.
- k)k)
- 4-(3-cloroanilino)-6-{4-[(1-dinetilamino-1-isopropilmetileno)amino}fenil)-7H-pirrolo[2,3-d]pirimidina; p.f. 255-257ºC, y4- (3-Chloroanilino) -6- {4 - [(1-dinetylamino-1-isopropylmethylene) amino} phenyl) -7H-pyrrolo [2,3-d] pyrimidine; m.p. 255-257 ° C, and
- l)l)
- 4-(3-cloroanilino)-6-(tiazol-2-il)-7H-pirrolo[2,3-d]pirimidina. 4- (3-Chloroanilino) -6- (thiazol-2-yl) -7H-pyrrolo [2,3-d] pyrimidine.
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5000 cápsulas que comprende cada una como ingrediente activo 0.25 g de uno de los compuestos de fórmula I mencionado en los agentes precedentes, se preparan como siguen:5000 capsules each comprising as active ingredient 0.25 g of one of the compounds of formula I mentioned in the preceding agents, they are prepared as follows:
Proceso de preparación: Las sustancias mencionadas son pulverizadas y forzadas a través de un tamiz con un tamaño de malla 0.6 mm. Porciones de 0.33 g de la mezcla se dispersan en cápsulas de gelatina utilizando una maquina de relleno de cápsula.Preparation process: The substances mentioned are pulverized and forced through a sieve with a 0.6 mm mesh size. 0.33 g portions of the mixture are dispersed in gelatin capsules using a filling machine of capsule.
5000 cápsulas de gelatina suave, que comprende cada una como ingrediente activo 0.05 g de uno de los compuestos de fórmula I mencionados en los ejemplos precedentes, se preparan como sigue:5000 soft gelatin capsules, comprising each as an active ingredient 0.05 g of one of the compounds of formula I mentioned in the preceding examples, are prepared as follow:
Proceso de preparación: el ingrediente activo pulverizado se suspende en Lauroglicol®(propilen glicol laurato, Gattefossé S.A., Saint Priest, Francia) y se muele en un pulverizador húmedo hasta un tamaño de partícula de aproximadamente 1 a 3 \mum. porciones de 0.419 g de la mezcla se dispensa entonces en cápsulas de gelatina suave utilizando una maquina de relleno de cápsula.Preparation process: the active ingredient powder is suspended in Lauroglycol® (propylene glycol laurate, Gattefossé S.A., Saint Priest, France) and is ground in a wet sprayer up to a particle size of approximately 1 to 3 µm. 0.419 g portions of the mixture is then dispensed in soft gelatin capsules using a filling machine capsule.
5000 cápsulas de gelatina suave que comprende cada una como ingrediente activo 0.05 g de uno de los compuestos de fórmula I mencionado en los ejemplos precedentes, se preparan como sigue:5000 soft gelatin capsules comprising each as an active ingredient 0.05 g of one of the compounds of Formula I mentioned in the preceding examples, are prepared as follow:
Proceso de reparación: el ingrediente activo pulverizado se suspende en PEG 400 (polietilenglicol que tiene un M_{r} de aproximadamente 380 a aproximadamente 420, Fluka, Suiza) y Tween®80 (polioxietileno sorbitan monolaurato, Atlas Chem. Ind. Inc., USA, suministrada por Fluka, Suiza) y se muele en un pulverizador húmedo a un tamaño de partícula de aproximadamente 1 a 3 \mum. porciones de 0.43 g de la mezcla son entonces dispensadas a cápsulas de gelatina suave utilizando una maquina de relleno de cápsula.Repair process: the active ingredient powder is suspended in PEG 400 (polyethylene glycol which has a M_ {r} from about 380 to about 420, Fluka, Switzerland) and Tween®80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland) and ground in a wet sprayer at a particle size of about 1 to 3 \ mum. 0.43 g portions of the mixture are then dispensed to soft gelatin capsules using a filling machine capsule.
Claims (7)
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- a)to)
- un radical de fórmula IIa radical of formula II
- En el cual u es 1 yIn which u is 1 and
- R_{4} es N^{3}-alquilureido inferior, N^{3}-fenilureido, N^{3}-alquiltioureido, alquilcarbonilamino inferior, benziloxicarbonilamino, morfolina-4-carbonilo, piperazina-1-carbonilo, 4alquilpiperazina inferior-1-carbonilo, alquilsulfonilamino inferior, benzenosulfonilamino, toluenosulfonilamino, furan-2-carbonilamino, tiofeno-2- carbonilamino, benzilamino, hidroximetil o un radical de fórmula -N=C(R_{5})-R_{6} es el cual R_{5} es hidrógeno o alquilo inferior y R_{6} es di-alquilamino inferior, piperidino, 4-alquilpiperazino o morfolino inferior, o esR_ {4} is N3-lower alkylureido, N3 -phenylureido, N3-alkylthioureido, alkylcarbonylamino lower, benzyloxycarbonylamino, morpholine-4-carbonyl, piperazine-1-carbonyl, 4alkylpiperazine lower-1-carbonyl, lower alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, furan-2-carbonylamino, thiophene-2-carbonylamino, benzylamino, hydroxymethyl or a radical of formula -N = C (R 5) - R 6 is which R 5 is hydrogen or lower alkyl and R 6 is di-lower alkylamino, piperidino, 4-alkylpiperazino or lower morpholino, or is
- b)b)
- un radical de fórmula IIIa radical of formula III
- en el cual R_{7} es alcoxi inferior y R_{8} es hidroxilo o benziloxi, o esin which R 7 is lower alkoxy and R 8 is hydroxy or benzyloxy, or is
- c)C)
- piperazino-1-carbonilo, 4-alquilpiperazino inferior-1-carbonilo, morfolino-4-carbonilo, tiocarbamoilo, tiazol-2-il, 4-(4-metoxifenil)tiazol-2-il, 4-etiltiazol-2-il, 4,5-dimetiltiazol-2-il, tetrazol-5-il, 2metiltetrazol-5-il o 1-metiltetrazol-5-il, o espiperazino-1-carbonyl, 4-alkylpiperazino lower-1-carbonyl, morpholino-4-carbonyl, thiocarbamoyl, thiazol-2-yl, 4- (4-methoxyphenyl) thiazol-2-yl, 4-ethylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, tetrazol-5-yl, 2 methyltetrazol-5-yl or 1-methyltetrazol-5-yl, or is it
- d)d)
- un radical de fórmula -CH=H-OR_{9} en el cual R_{9} es hidrógeno o alquilo inferior, ya radical of formula -CH = H-OR9 in which R9 it is hydrogen or lower alkyl, and
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- a)to)
- hacer reaccionar un derivado de pirrolo[2,3-d]pirimidina de la fórmula IVdo react a derivative of pyrrolo [2,3-d] pyrimidine of the formula IV
- en la cual X es un grupo saliente adecuado, Z es hidrógeno o 1-aril-alquilo inferior y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en los radicales R_{1} y R_{2} si es necesario están protegidos por grupos protectores, con un derivado de anilina de la fórmula Vin which X is a suitable leaving group, Z is hydrogen or 1-aryl-lower alkyl and the others substituents are as defined above for the compounds of formula I, the free functional groups present in the radicals R 1 and R 2 if necessary are protected by protecting groups, with an aniline derivative of the formula V
- en la cual R, R_{3} n y q son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores fácilmente removibles, y remover los grupos protectores presentes y, si están presente, el radical 1-aril-alquilo inferior Z, oin which R, R 3 n and q are as defined above for the compounds of formula I, the free functional groups present in the radical R if necessary they are easily protected by protective groups removable, and remove the protective groups present and, if they are present, the 1-aryl-alkyl radical lower Z, or
- b)b)
- hacer reaccionar un derivado de pirrolo[2,3-d]pirimidin-4-ona de la fórmula VIdo react a derivative of pyrrolo [2,3-d] pyrimidin-4-one of formula VI
- en la cual Z' es 1-aril-alquilo inferior y R_{1} y R_{2} son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en los radicales R_{1} y R_{2} si es necesario están protegidos por grupos protectores, en la presencia de un agente deshidratante y una amina terciaria, con una fenilamina de la fórmula V anterior y removiendo los grupos protectores presentes, oin which Z 'is 1-aryl-lower alkyl and R 1 and R2 are as defined above for the compounds of formula I, the free functional groups present in the radicals R_ {1} and R2_ if necessary are protected by groups protectors, in the presence of a dehydrating agent and an amine tertiary, with a phenylamine of the formula V above and stirring the protective groups present, or
- e)and)
- para la preparación de un compuesto de fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula -CH=N-OR_{9} en el cual R_{9} es hidrógeno o alquilo inferior, y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es formilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con un derivado de hidroxilamina de la fórmula VIIIfor the preparation of a compound of formula I in which one of the radicals R1 and R2 is a radical of the formula -CH = N-OR9 in which R9 is hydrogen or lower alkyl, and the other substituents are as defined above for the compounds of formula I, reacting a compound of formula I, in which one of the radicals R1 and R2 is formyl and the other substituents are as defined. above for the compounds of formula I, the groups functional functions present in the radical R if necessary are protected by protecting groups, with a hydroxylamine derivative of formula VIII
- en la cual R_{12} es hidrógeno o alquilo inferior, y remover los grupos protectores presentes, oin which R 12 is hydrogen or lower alkyl, and remove the groups protectors present, or
- f)F)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es piperidina-1-carbonilo, piperazina-1-carbonilo, 4-alquilpiperazina inferior-1-carbonilo o moforlino-4-carbonilo, y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es carboxilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, o un derivado de ácido carboxílico reactivo de tal compuesto, con una amina de la fórmula VIIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is piperidine-1-carbonyl, piperazine-1-carbonyl, 4-alkylpiperazine lower-1-carbonyl or moforlino-4-carbonyl, and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is carboxyl and the others substituents are as defined above for the compounds of formula I, the free functional groups present in the radical R if necessary they are protected by protective groups, or a derivative of reactive carboxylic acid of such compound, with a amine of formula VII
- en la cual los radicales R_{10} y R_{11} juntos son pentano-1,5-diilo, 3-azapentano-1,3-diilo, 3-N-alquilo inferior-3-azapentano-1,3-diilo o 3-oxapentano-1,3-diilo, y luego remover los grupos protectores presentes, oin which the radicals R 10 and R 11 together are pentane-1,5-diyl, 3-azapentane-1,3-diyl, 3-N-alkyl lower-3-azapentane-1,3-diyl or 3-oxapentane-1,3-diyl, and then remove the protective groups present, or
- g)g)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es tiocarbamoilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es aminocarbonilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos mediante grupos protectores, con el reactivo de Lawesson, y luego remover los grupos protectores presentes, ofor the preparation of a compound of the formula I in which one of the radicals R 1 and R 2 is thiocarbamoyl and the others substituents are as defined above for the compounds of formula I, reacting a compound of formula I, in which one of the radicals R 1 and R 2 is aminocarbonyl and the other substituents are as defined above for the compounds of formula I, the free functional groups present in the radical R if necessary are protected by groups protectors, with Lawesson's reagent, and then remove the protective groups present, or
- h)h)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es R_{13}-tiazol-2-ilo en el cual R_{13} en cada caso es etilo o alcoxifenilo inferior y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es tiocarbamoilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con un compuesto de la fórmula IXfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is R 13 -thiazol-2-yl in which R 13 in each case is ethyl or lower alkoxyphenyl and the other substituents are as defined above for the compounds of formula I, reacting a compound of formula I, in which one of the radicals R_ {1} and R2_ is thiocarbamoyl and the other substituents are as defined above for the compounds of formula I, the groups functional functions present in the radical R if necessary are protected by protecting groups, with a compound of the formula IX
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- en el cual X es un grupo saliente y R_{13} en cada caso es etilo o alquilfenilo inferior, los grupos funcionales libres presentes en el radical R_{13} si es necesario están protegidos por grupos protectores, y luego remover los grupos protectores presentes, oin which X is a leaving group and R 13 in each case is ethyl or alkylphenyl lower, the free functional groups present in the radical R_ {13} if necessary are protected by protective groups, and then remove the protective groups present, or
- i)i)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es tetrazol-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es ciano y los otros sustituyentes son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con una acida de metal alcalino adecuada, y luego remover los grupos protectores presentes, ofor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is tetrazol-5-yl and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is cyano and the others substituents are as defined above for the compounds of the formula I, the free functional groups present in the radical R if necessary are protected by protective groups, with a suitable alkali metal acid, and then remove the protective groups present, or
- j)j)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es 2-alquiltetrazol inferior-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de fórmula I, en el cual uno de los radicales R_{1} y R_{2} es tretrazol-5-ilo y los otros sustituyentes son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R si es necesario están protegidos por grupos protectores, con el yoduro de alquilo inferior apropiado, y luego remover los grupos protectores presentes, ofor the preparation of a compound of the formula I in which one of the radicals R 1 and R 2 is 2-alkyltetrazole lower-5-ilo and the others substituents are as defined above for the compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is tretrazol-5-yl and the others substituents are as defined above for the compounds of the formula I, the free functional groups present in the radical R if necessary are protected by protective groups, with the appropriate lower alkyl iodide, and then remove the protective groups present, or
\newpage\ newpage
- k)k)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en el cual por lo menos un radical R_{4} es alquilsulfonilamino inferior, bencenosulfonilamino o toluenosulfonilamino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario son protegidos al remover fácilmente los grupos protectores, con un compuesto de fórmula Xin which by at least one radical R 4 is lower alkylsulfonylamino, benzenesulfonylamino or toluenesulfonylamino and the others Substituents and symbols are as defined above for the compounds of formula I, reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in which at least one radical R 4 is amino and the other substituents and symbols are as defined above for the compounds of the formula I, the groups functional functions present in the radical R and, if present, the other radicals R_ {4} if necessary are protected by easily remove the protective groups, with a compound of formula X
- en el cual X es cloro o bromo y R_{14} es alquilo inferior, fenilo o 4-metilfenilo, y luego remover los grupos protectores presentes, oin which X is chlorine or bromine and R 14 is lower alkyl, phenyl or 4-methylphenyl, and then remove the groups protectors present, or
- l)l)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en la cual por lo menos un radical R_{4} es un radical de la fórmula -N=C(R_{5})-R_{6} en el cual R_{5} es hidrógeno y R_{6} es como se definió anteriormente para los compuestos de la fórmula I y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario son protegidos al remover fácilmente los grupos protectores, con un acetal de la fórmula XIin which by at least one radical R4 is a radical of the formula -N = C (R 5) - R 6 in which R 5 is hydrogen and R 6 is as defined above for the compounds of the formula I and the other substituents and symbols are as defined above for the compounds of formula I, by reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of the formula II in the which at least one radical R4 is amino and the others Substituents and symbols are as defined above for the compounds of formula I, the free functional groups present in the radical R and, if present, the other radicals R4 if necessary they are protected by easily removing the groups protectors, with an acetal of the formula XI
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- en la cual R_{15} y R_{16} son cada uno individualmente alquilo inferior o juntos son pentano-1,5-diilo, 3-N-alquilo inferior-3-azapentano-1,5-diilo o 3-oxapentano-1,5-diilo, y R_{17} es alquilo inferior, y luego remover los grupos protectores presentes, oin which R 15 and R 16 are each individually lower alkyl or together they are pentane-1,5-diyl, 3-N-alkyl lower-3-azapentane-1,5-diyl or 3-oxapentane-1,5-diyl, and R 17 is lower alkyl, and then remove the groups protectors present, or
- m)m)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- en la cual por lo menos un radical R_{4} es N^{3}-alquilureido inferior o N^{3}-fenilureido y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario son protegidos mediante grupos protectores fácilmente removibles, con un isocianato de la fórmula XIIin which by at least one radical R 4 is N 3 -alkylureido lower or N3 -phenylureido and the others Substituents and symbols are as defined above for the compounds of formula I, reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in which at least one radical R 4 is amino and the other substituents and symbols are as defined above for the compounds of the formula I, the groups functional functions present in the radical R and, if present, the other radicals R 4 if necessary are protected by easily removable protective groups, with an isocyanate of the formula XII
- en el cual R_{18} es alquilo o fenilo inferior, y luego remover los grupos protectores presentes, oin which R 18 is lower alkyl or phenyl, and then remove the groups protectors present, or
\newpage\ newpage
- n)n)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en el cual por lo menos un radical R_{4} es N^{3}-alquiltioureido inferior o N^{3}-feniltioureido y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario son protegidos mediante grupos protectores fácilmente removibles, con un isotiocianato de la fórmula XIIIin which by at least one radical R_ {4} is N 3 -alkylthioureido lower or N3 -phenylthioureido and the other substituents and Symbols are as defined above for compounds of formula I, by reacting a compound of formula I, in the which one of the radicals R1 and R2 is a radical of formula II in which at least one radical R 4 is amino and the Other substituents and symbols are as defined above. for the compounds of the formula I, the free functional groups present in the radical R and, if present, the others radicals R_ {4} if necessary are protected by groups easily removable protectors, with an isothiocyanate of the formula XIII
- en la cual R_{18} es alquilo o fenilo inferior, y luego remover los grupos protectores presentes, oin which R 18 is lower alkyl or phenyl, and then remove the groups protectors present, or
- o)or)
- para la preparación de un compuesto de la fórmula I en el cual uno de los radicales R_{1} y R_{2} es un radical de la fórmula IIfor the preparation of a compound of the formula I in which one of the radicals R1 and R2 is a radical of formula II
- en la cual por lo menos un radical R_{4} es alcoxicarbonilamino inferior o benziloxicarbonilamino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de fórmula I, haciendo reaccionar un compuesto de la fórmula I, en el cual uno de los radicales R_{1} y R_{2} es un radical de fórmula II en el cual por lo menos un radical R_{4} es amino y los otros sustituyentes y símbolos son como se definió anteriormente para los compuestos de la fórmula I, los grupos funcionales libres presentes en el radical R y, si están presentes, los otros radicales R_{4} si es necesario son protegidos mediante grupos protectores fácilmente removibles, con un éster de ácido clorofórmico de la fórmula XIVin which by at least one radical R 4 is lower alkoxycarbonylamino or benzyloxycarbonylamino and the other substituents and symbols are as defined above for the compounds of formula I, by reacting a compound of the formula I, in which one of the radicals R 1 and R 2 is a radical of formula II in the which at least one radical R4 is amino and the others Substituents and symbols are as defined above for the compounds of formula I, the free functional groups present in the radical R and, if present, the other radicals R4 if necessary they are protected by protective groups easily removable, with an ester of chloroformic acid from the formula XIV
- en el cual R_{18} es alquilo o bencilo inferior, y luego remover los grupos protectores presentes,in which R 18 is alkyl or lower benzyl, and then remove the groups protectors present,
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CH2071/96 | 1996-08-23 | ||
CH207196 | 1996-08-23 |
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ES2297864T3 true ES2297864T3 (en) | 2008-05-01 |
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ES97940108T Expired - Lifetime ES2297864T3 (en) | 1996-08-23 | 1997-08-21 | REPLACED PIRROLOPIRIMIDINES AND PROCESSES FOR THEIR PREPARATION. |
Country Status (11)
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US (1) | US6180636B1 (en) |
EP (1) | EP0938486B1 (en) |
JP (1) | JP4242928B2 (en) |
AT (1) | ATE384062T1 (en) |
AU (1) | AU720429B2 (en) |
CA (1) | CA2262421C (en) |
DE (1) | DE69738468T2 (en) |
DK (1) | DK0938486T3 (en) |
ES (1) | ES2297864T3 (en) |
PT (1) | PT938486E (en) |
WO (1) | WO1998007726A1 (en) |
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- 1997-08-21 ES ES97940108T patent/ES2297864T3/en not_active Expired - Lifetime
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- 1997-08-21 PT PT97940108T patent/PT938486E/en unknown
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- 1997-08-21 DE DE69738468T patent/DE69738468T2/en not_active Expired - Lifetime
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JP2000516626A (en) | 2000-12-12 |
CA2262421A1 (en) | 1998-02-26 |
JP4242928B2 (en) | 2009-03-25 |
CA2262421C (en) | 2007-10-02 |
ATE384062T1 (en) | 2008-02-15 |
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